Increased risk of haematological malignancy in adults over age 60 with thrombocytopenia compared with matched controls: Time for an upfront bone marrow evaluation?

International societies have conflicting recommendations on whether bone marrow aspirate/biopsy (BMB) is needed during workup for isolated thrombocytopenia. Our objective was to determine if thrombocytopenia in patients aged ≥60 years is associated with an increased incidence of haematological malignancy. We performed a retrospective population-based cohort study in patients aged ≥60 years between January 1, 2009 to December 31, 2019. Exposed patients had specialist consultation for thrombocytopenia, with platelet count <100 × 109/L, but normal haemoglobin and white blood cell count. Unexposed patients were those who never had specialist consultation for thrombocytopenia and whose platelets were ≥100 × 109/L. The primary outcome was the diagnosis of haematological malignancy using a competing risk of death model. During 4.0 years (IQR 2.2-6.7) of follow-up, 378/4930 exposed (19.1/1000PY, 95% CI 17.1-21.0), and 204/17556 unexposed patients (2.5/1000PY, 95% CI 2.2-2.8) were diagnosed with haematological malignancy (HR 15.5 (95% CI 11.3-21.4, p < 0.0001) in year 1, and 5.3 (95% CI 4.4-6.6, p < 0.0001) in years 2+). This finding persisted in analyses stratified by sex, age, severity, or duration of thrombocytopenia, and treatment with corticosteroids within 2 weeks of consultation. This study found a strong association between isolated thrombocytopenia and haematological malignancy in patients ≥60 years, supporting consideration of diagnostic testing including BMB during outpatient specialist consultation.

Blockade of clearance of immune complexes by an anti-Fc gamma receptor monoclonal antibody.

Clearance of immune complexes by the mononuclear phagocyte system is important for maintaining normal host defenses against bacterial and viral assault (1), but also contributes to the pathogenesis of a variety of immune- mediated diseases . For example, removal from the circulation of IgG-coated erythrocytes and platelets by the MPS is the sine qua non of immune-mediated cytopenias (2, 3). On the other hand, abnormally decreased removal by the MPS of smaller, soluble immune complexes may play a role in the pathogenesis of immune complex-mediated tissue damage found in such autoimmune diseases as SLE (4). Although the physicochemical nature and the size of immune complexes can influence rates of clearance and sites of deposition (reviewed in 5), interactions between immune complexes and the MPS in vivo are poorly understood. The inability to directly measure binding or internalization of immune complexes by cells in the liver and spleen has made the analysis of the molecular basis of immune complex clearance very difficult . Receptors for the Fc portion of IgG (FcgammaR) and for complement (CR) undoubtedly play a role in the removal of immune complexes, but the relative importance of these receptors is not known.

6th International Immunoglobulin Symposium: poster presentations.

The posters presented at the 6th International Immunoglobulin Symposium covered a wide range of fields and included both basic science and clinical research. From the abstracts accepted for poster presentation, 12 abstracts were selected for oral presentations in three parallel sessions on immunodeficiencies, autoimmunity and basic research. The immunodeficiency presentations dealt with novel, rare class-switch recombination (CSR) deficiencies, attenuation of adverse events following IVIg treatment, association of immunoglobulin (Ig)G trough levels and protection against acute infection in patients with X-linked agammaglobulinaemia (XLA) and common variable immunodeficiency (CVID), and the reduction of class-switched memory B cells in patients with specific antibody deficiency (SAD). The impact of intravenous immunoglobulin on fetal alloimmune thrombocytopenia, pregnancy and postpartum-related relapses in multiple sclerosis and refractory myositis, as well as experiences with subcutaneous immunoglobulin in patients with multi-focal motor neuropathy, were the topics presented in the autoimmunity session. The interaction of dendritic cell (DC)-SIGN and alpha2,6-sialylated IgG Fc and its impact on human DCs, the enrichment of sialylated IgG in plasma-derived IgG, as wells as prion surveillance and monitoring of anti-measles titres in immunoglobulin products, were covered in the basic science session. In summary, the presentations illustrated the breadth of immunoglobulin therapy usage and highlighted the progress that is being made in diverse areas of basic and clinical research, extending our understanding of the mechanisms of immunoglobulin action and contributing to improved patient care.

Human megakaryocytes. VII. Analysis of megakaryocytes for nuclear DNA content distribution in whole marrow cell suspensions by flow cytometry.

These studies were designed to quantitate and determine the DNA content distribution of human marrow megakaryocytes using whole bone marrow. Cellular DNA content within megakaryocytic cells was established by measuring propidium iodide staining in marrow cells expressing platelet glycoprotein IIb/IIIa (Gp IIb/IIIa). These studies were based on the development of a method for rapid analysis of whole marrow cell preparations by a dual fluorescent system. DNA values ranging from 2 to 64 C were observed in all samples tested, with 16 C corresponding to the modal ploidy class representing almost one-half of the cells containing Gp IIb/IIIa. The second most frequent ploidy class corresponded to 32 C, followed by 8 C, with 20% and 15%, respectively. Virtually all high-ploidy megakaryocytes (greater than or equal to 8 C) were of low density (less than 1.050 g/cm3), whereas 2 and 4 C megakaryocytes were evenly distributed between less than or equal to 1.050 and greater than 1.050 g/cm3 marrow cells. These studies conclusively establish DNA content distribution of normal human marrow megakaryocytes and provide a basis for the study of states of altered megakaryocytopoiesis.

Novel approaches to refractory immune thrombocytopenic purpura.

Chronic immune thrombocytopenic purpura (ITP) is an organ-specific autoimmune bleeding disorder in which autoantibodies are directed against the individual's own platelets, resulting in increased Fc-mediated platelet destruction by macrophages in the reticuloendothelial system. Although ITP is primarily mediated by IgG autoantibodies, the production of these autoantibodies is regulated by the influence of T lymphocytes and antigen-presenting cells (APC). There is evidence that enhanced T-helper cell/APC interactions in patients with ITP may play an integral role in IgG antiplatelet autoantibody production. New therapies may improve platelet production, decrease platelet antibody production, and decrease monocyte function and/or B-cell and T-cell activities. Understanding these cellular immune responses in ITP may lead to the development of more specific immunoregulatory therapies for the management of this disease.

Fetal and neonatal thrombocytopenia.

Thrombocytopenia is defined as platelet count less than 150,000 plat/mm3. Etiologic factors involved include immunological (NAIT and ITP), fetal infectious disease, chromosomal and nonchromosomal, and miscellaneous causes. While the understanding of fetal thrombocytopenia is driven by reason to do fetal blood sampling, discovery of neonatal thrombocytopenia is driven by blood counts performed because of the risk of infections. The most serious consequence of thrombocytopenia in the fetus/neonate is intracranial hemorrhage which can occur in utero as early as 18 weeks gestation. The key factor in perinatal prevention of intracranial hemorrhage is early diagnosis and treatment, possibly in utero. Cordocentesis under direct ultrasound guidance and platelet transfusions have played a major role in the management of fetal/neonatal thrombocytopenia. Ongoing studies and high resolution ultrasound will continue to explore and hopefully clarify fetal and neonatal thrombocytopenia and facilitate recognition of primary and secondary thrombocytopenias.

Splenectomy-sparing strategies for the treatment and long-term maintenance of chronic idiopathic (immune) thrombocytopenic purpura.

Patients with idiopathic thrombocytopenic purpura (ITP) have vulnerability to additional bleeding, leaving them susceptible to severe hemorrhaging. Low platelet counts contribute to this rare, but significant outcome, but may not be the sole determinant. Although the only current treatment of ITP felt to be curative is surgical removal of the spleen, the long-term outcome for these patients is not well defined. Our group Investigated the use of Intravenous gamma-globulin in the treatment of children with chronic ITP as a means to defer splenectomy. A variation of this approach uses anti-D to block splenic macrophages with antibody-coated red blood cells. There may be a correlation between response to anti-D and response to splenectomy in adults with ITP. Because the long-term results of splenectomy are not well defined, additional clinical studies are warranted. Questions requiring further study Include whether repeated Infusions of anti-D could allow the postponement and ultimate avoidance of splenectomy and whether the role of anti-D may be for pregnant women who are not readily eligible for splenectomy. Such an analysis should include information on the long-term outcome of splenectomy as well as information on whether patients have a durable improvement. Such studies about the potential outcomes of splenectomy and of avoidance of splenectomy will help identify new treatment strategies that may help to eliminate the need for this procedure in patients with chronic ITP.

Fc receptor blockade and immune thrombocytopenic purpura.

Inhibition of antibody-coated platelet destruction in patients with immune thrombocytopenic purpura (ITP) is a well-known mechanism of treatment effect. A number of interventions that would ameliorate the thrombocytopenic effect of ITP patient plasma when infused into normal recipients were demonstrated in 1965. Subsequently, the antibody-coated chromium-labeled red blood cell clearance study was developed to allow direct in vivo assessment of Fc receptor (FcR) blockade. This was first demonstrated for corticosteroids but more extensive investigation began with the study of intravenous infusions of gammaglobulin (IVIg). The unequivocal demonstration of FcR blockade following IVIg Initiated novel approaches. One involved the infusion of a monoclonal anti-FcRIII ligand-blocking antibody into patients with refractory ITP. The efficacy of this treatment demonstrated that FcR blockade was not an epiphenomenon but rather an important mechanism of the increase in the platelet count in patients with ITP. Confirmation of its importance was obtained from the infusion of intravenous (IV) anti-D and the use of the isolated Fc piece of IgG. Recent studies have begun to explore the possibility of a monoclonal anti-FcRI and monoclonal anti-Ds. In summary, FcR blockade is an important mechanism of treatment effect in patients with ITP. Cytokine release as a consequence of this interaction and other immunomodulatory effects have only begun to be studied.

Clinical experience with anti-D in the treatment of idiopathic thrombocytopenic purpura.

Idiopathic thrombocytopenic purpura (ITP), an autoimmune disease of children and adults, is characterized by low platelet counts and bleeding through mucous membranes. While not uncommon among otherwise healthy adults and children, ITP is a frequent complication of human immunodeficiency virus (HIV) infection. Anti-D is a gamma globulin (IgG) fraction containing a high proportion of antibodies to the Rh0 (D) antigen of the red blood cells. Clinical studies over the past 10 years have shown intravenous anti-D to be a safe and effective treatment for Rh-positive, nonsplenectomized patients with ITP (classic or HIV-related). While it is unlikely that anti-D is a curative treatment for ITP, repeated infusions can be used to maintain the platelet count at a level sufficient to provide adequate hemostasis (>30,000/microL) and may enable patients to postpone or even avoid splenectomy.

Idiopathic thrombocytopenia purpura: Treatment patterns and an analysis of cost associated with intravenous immunoglobulin and anti-D therapy.

A retrospective study was conducted to determine treatment patterns for idiopathic thrombocytopenia purpura (ITP) across the US and to determine the cost of its treatment with high-dose intravenous immunoglobulin (IVIg) and anti-D therapy. Information on the incidence, treatment patterns, hospital care, and costs for ITP was derived from three data bases and supplemented by in-depth case studies from five hospital centers in the US. Data collection forms were developed to collect data on treatment patterns and costs at the five hospital centers. Treatment patterns were analyzed and used to model the comparative costs of IVIg and anti-D therapy. Cost estimations were based on a process and cost-finding analysis reflecting current practice patterns for the use of IVIg and anti-D therapy in an outpatient clinic. The incidence of ITP was estimated at 65 per 10,000 in human immunodeficiency virus (HIV)-positive individuals and 1.5 per 10,000 in HIV-negative individuals. Hospital discharge data from all 1991 and 1992 hospital discharges in Maryland revealed that both Medicare patients and patients who had other payment options spent less time in hospital compared to Medicaid patients. The limited case study data indicate that anti-D therapy increased platelet counts to greater than 25,000/microL in 82% of evaluable episodes and that IVIg-treated patients reached 25,000/microL in 48% of treated episodes. The estimated cost per treated episode of ITP was $4,269 for IVIg and $2,716 for anti-D therapy, reflecting a cost savings of $1,553 per episode. This retrospective study has shown that the use of anti-D therapy is associated with lower costs compared with IVIg treatment in patients with ITP. The shorter infusion time required for anti-D therapy may also contribute to a better quality of life for patients.

The potential for treatment of idiopathic thrombocytopenic purpura with anti-D to prevent splenectomy: a predictive cost analysis.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder affecting both children and adults that can be manifested by severe bleeding episodes. Adult ITP patients have a low rate of spontaneous remission, and symptomatic patients commonly undergo splenectomy; however, maintenance therapy may increase the rate of remission, allowing splenectomy to be avoided. Anti-D is a recently licensed treatment for ITP that has the potential to delay, and possibly avoid, the need for splenectomy. We used preliminary data from an ongoing clinical trial to evaluate the costs involved in using anti-D therapy for 1 year with the intent of avoiding the need for splenectomy. We accounted for different possible outcomes at the completion of the clinical trial. An economic model with a theoretical cohort of 100 patients was developed using the model of an ongoing clinical trial. The average wholesale price was used to determine the cost of an infusion of anti-D based on an average dose ($1,213 per infusion). The cost of splenectomy was determined by a literature review ($16,000). Costs were calculated for all known patient outcomes; where outcomes were unknown and likely to vary, all possible outcomes were accounted for (splenectomy or no splenectomy). In our theoretical cohort, 31 of 100 patients were taken off anti-D and received splenectomy, 32 of 100 were stable after receiving anti-D and would not need splenectomy, and 37 of 100 had Indeterminate outcomes after receiving anti-D. When compared with the cost of the hypothetical scenario of initially giving all 100 patients splenectomy ($1.6 million), a minimum of 47 patients would have to avoid splenectomy to result in a cost savings for our cohort of 100 patients. The group of 47 patients avoiding splenectomy would be composed of the 32 patients comprising the stable group and at least 15 of the 37 patients comprising the group with indeterminate outcomes. If all 37 of the patients in the group with indeterminate outcomes avoid splenectomy, $363,000 and 69 spleens would be saved. Our data suggest that in the phase III trial of maintenance anti-D therapy versus immediate splenectomy, anti-D therapy will be a cost-effective option if 47% or more of patients avoid splenectomy.

Autoimmune neutropenia of childhood.

Autoimmune neutropenia (AIN) of infancy is an underreported disease because of its benign nature. In addition, the relative unavailability of neutrophil antibody testing prevents confirmation of suspected diagnoses. Small children do not have life-threatening infections, do not have associated diseases, respond to i.v. gamma globulin with increased neutrophil counts, and tend to improve on their own. Older children with AIN have associated diseases such as hepatitis or Hodgkin's disease, often have other immune cytopenias, and respond poorly to any therapy. Immune deficiency states, especially those of the humoral arms, are associated with development of AIN.

Overview of idiopathic thrombocytopenic purpura: new approach to refractory patients.

Idiopathic thrombocytopenic purpura is a disorder in which autoantibodies are made to platelets, resulting in accelerated platelet destruction. The diagnosis may be made in outpatients who are previously well or in patients with multiple medical conditions and medications. There are no unequivocal ways to distinguish immune thrombocytopenias from other thrombocytopenias, even with state-of-the-art tests including anti-platelet antibodies, thrombopoietin, glycocalicin, and platelet reticulocyte counts. Clinical evaluation includes ruling out a systemic process such as a viral infection or leukemia. Treatment of idiopathic thrombocytopenic purpura should be individualized. Substantial platelet increases are seen in more than 50% of patients who receive intravenous IgG, intravenous anti-D, steroids, or splenectomy. Two additional agents showing promising clinical trial experience are anti-CD40 ligand and rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA).

Concurrence of von Willebrand's disease and hemophilia A: implications for carrier detection and prevalence.

Five families with concurrent von Willebrand's disease (VWD) and classic hemophilia (hemophilia A) are described. Three were ascertained through women undergoing hemophilia carrier testing, one through an obligate carrier who also has VWD, and one through the affected father of a hemophiliac. The VWD probands exhibited Type I VWD with reduced Factor VIII-related antigen (VIIIR:Ag) and/or von Willebrand factor on more than one occasion, normal VIIIR:Ag on crossed immunoelectrophoresis, and mild symptoms. No male had both disorders, but two obligate hemophilia carriers also had VWD. Neither was detectable as a carrier by discriminant analysis. Four possible carriers of hemophilia had VWD and would also be classified as noncarriers statistically. These findings suggest that the presence of VWD may invalidate hemophilia carrier testing by conventional methods. The independent entry into the family of the two genes by mating of a hemophilia carrier and a VWD male is documented in two cases and probable in two. The observed frequency of such matings supports the hypothesis that VWD is a common disorder.

Immune thrombocytopenia in pregnancy: autoimmune and alloimmune.

Auto- and alloimmune thrombocytopenias in pregnancy may seriously impact on both mother and fetus. Autoimmune thrombocytopenia (ITP) affects both mothers and fetuses but is considered to be quite benign for both groups. The 'facts' are that: 1) ITP occurs commonly in pregnancy; 2) there has been no reported maternal mortality in more than 20 years; 3) management, except at delivery, is similar to management in the non-pregnant state; 4) splenectomy is virtually never required during pregnancy; 5) significant neonatal thrombocytopenia occurs in approximately 10% of cases and intra-cranial hemorrhage (ICH) 1%; 6) the course of the first sibling predicts that of the next sibling; and 7) the fetal platelet count can be successfully determined (if desired) by either fetal blood sampling (FBS) or by fetal scalp sampling. Many other important considerations remain undetermined: 1) non-invasive prediction of severe fetal thrombocytopenia; 2) the appropriate mode of delivery for a thrombocytopenic fetus; 3) the role of anti-platelet antibody testing; and 4) the effects on the fetal platelet count of maternal therapy. Alloimmune thrombocytopenia (AIT) is easier to outline because it is a far more serious fetal disorder: 1) neonatal platelet counts < 20,000/microliter are common in AIT; 2) there is a 10-30% ICH rate in first affected newborns, some of which occur antenatally; 3) there is no universal prenatal screening although this would be scientifically feasible; 4) testing is complex and requires an experienced laboratory that can test at least five platelet antigens and has sufficient typed controls to confirm the specificity of any anti-platelet antibodies detected; 5) the second affected sibling in a family is usually more severely affected than the first; 6) treatment of the thrombocytopenic neonate can be accomplished with intravenous (i.v.) gammaglobulin and/or platelet transfusions; and 7) treatment of the fetal platelet count can be accomplished in most instances by infusing the mother with i.v. gammaglobulin with or without steroids; platelet transfusions to the fetus is another option.

Comparison of platelet counts in first and second newborns of mothers with immune thrombocytopenic purpura.

OBJECTIVE: This study was designed to estimate the predictive value of the first neonatal platelet count for the second neonate in women with immune thrombocytopenic purpura (ITP). METHODS: Data of 34 patients, repeatedly pregnant while they had ITP, were prospectively collected in two study centers between 1984 and 1995. The main outcome measure was neonatal thrombocytopenia. RESULTS: Early neonatal platelet counts (i.e., umbilical cord count or count during the first 24 hours of life) between siblings were correlated (r = .73; 95% confidence interval (CI) for the correlation coefficient 0.52, 0.86). Severe thrombocytopenia (less than 50 x 10(9)/L) at birth did not occur in any of the 27 siblings of infants with birth platelet levels above 50 x 10(9)/L. Also the second sibling's nadir neonatal platelet counts during the first 2 weeks of life were correlated with those of the first sibling (r = .76; 95% CI for the correlation coefficient 0.58, 0.88). In those cases in which the first sibling had a lowest platelet count above 100 x 10(9)/L (n = 19), the second sibling never became thrombocytopenic. CONCLUSION: The platelet count of the first sibling can be used to counsel women with ITP, and may be helpful in their management.

Antenatal treatment of alloimmune thrombocytopenia.

OBJECTIVE: Neonatal alloimmune thrombocytopenia is caused by platelet antigen incompatibility between the mother and fetus. Affected fetuses may have severe thrombocytopenia leading to intracranial hemorrhage before or at birth. We sought to treat this condition in utero to prevent these hemorrhages. METHODS: Eighteen women who had previously delivered infants with severe alloimmune thrombocytopenia were treated with weekly infusions of intravenous gamma globulin from the diagnosis of fetal thrombocytopenia until birth; nine were also treated with corticosteroids. RESULTS: There were no intracranial hemorrhages in the treated fetuses, compared with ten cases among the 21 untreated siblings (48%). Only three treated fetuses, compared with 16 of 20 untreated siblings, had platelet counts of less than 30,000/microL, with no bleeding complications. CONCLUSION: Antenatal treatment of alloimmune thrombocytopenia with weekly gamma globulin effectively improves the fetal platelet count and prevents intracranial hemorrhage.

Autoimmune thrombocytopenic purpura.

The classic therapies of ITP are corticosteroids and splenectomy. These therapies will suffice to treat the majority of patients. In any patient with ITP in whom an urgent rise in the platelet count is required, especially children with acute ITP at diagnosis, gammaglobulin in combination with corticosteroids is very effective. In children with persistent ITP, avoiding splenectomy by using IVGG maintenance has been shown to be an effective form of therapy. For adults, most patients will be adequately treated by a short course of steroids followed by splenectomy, if needed. Other treatments are most needed in those adults whose ITP fails to respond to splenectomy or those who have special conditions. Danazol, vinca alkaloids, oral cyclophosphamide, and IVGG appear to be effective as chronic maintenance therapies, especially of splenectomized patients who are still thrombocytopenic. The role of newer therapies such as staph protein A pheresis and intravenous anti-D remains to be more completely explored.

Intravenous immunoglobulin therapy of idiopathic thrombocytopenic purpura in childhood and adolescence.

Intravenous immunoglobulin is not only a dramatic clinical therapy, but it is also extremely interesting in regard to mechanism of action. The high cost of therapy limits its application, yet it appears to be equal to or perhaps slightly more effective than corticosteroids as a treatment of ITP and is far less toxic with prolonged use. The appropriate place for its exact use remains to be determined but probably includes patients urgently requiring rapid platelet increases (in conjunction with steroids), treatment of immunocompromised patients, and treatment of chronic patients, either children to avoid splenectomy or adults with severe disease after splenectomy. Controlled trials to resolve these clinical questions are urgently needed. Existing studies on its mechanisms of actions are very interesting and have furthered our understanding of the pathophysiology of ITP. Although future work may lead to further applications, initial enthusiasm for the use of IVGG in the treatment of other autoimmune diseases with the exception of myasthenia gravis has been limited by subsequent clinical experience.

Fetal transfusion therapy.

Rapid advances are occurring in the diagnosis and treatment of the fetus with a red blood cell or platelet cytopenia. Noninvasive methods of monitoring the alloimmunized pregnancy, invasive methods such as amniocentesis and cordocentesis, and intrauterine transfusion therapy of both red cells and platelets, are being further refined to allow the prompt recognition and treatment of fetal cytopenias. Specialized centers have now accrued a large experience in the management of the fetus severely affected by alloimmunization. Advances in ultrasound, blood banking techniques, and genetic engineering technology have spurred the most recent advances. The indications for diagnosis, timing and frequency of invasive procedures for treatment, and technical considerations regarding preparation of blood products and volume of transfusion, are outlined in this review. Polymerase chain reaction (PCR) determination of fetal Rh(D) genotype by chorionic villus sampling or amniocentesis in the first or second trimesters is a recent clinically useful advance. The advent of hematopoietic stem cell transplantation and the potential for gene therapy are exciting advances in the treatment and prevention of hematopoietic diseases, including, but not limited, to the fetal cytopenias.