Levels Of Platelet-associated IgG Research Articles

Clinical characteristics, treatment, and outcomes of nivolumab induced immune thrombocytopenia.

Immune thrombocytopenia (ITP) represents an uncommon hematological side effect associated with nivolumab, and its distinct clinical attributes remain poorly defined. This research aimed to explore the clinical manifestations and outcomes of ITP induced by nivolumab. Reports on nivolumab induced ITP up to April 30, 2024, were collected for retrospective analysis. The study involved 34 patients with a median age of 67 years (range 32, 82). The onset of ITP varied from 10 to 100 days post initial dosage, with a median onset at 70 days. The majority of patients exhibited no symptoms, with only 23.5% experiencing clinically significant bleeding and 11.8% facing non-clinically significant bleeding. The median platelet count was 12 × 109/L (range 0, 115), with 67.6% of patients having platelet levels below 25 × 109/L. Bone marrow biopsy revealed mainly elevated megakaryocytes. Platelet-associated IgG levels were elevated with a median of 210 ng/107 cells (range 73, 1130). Subsequent interventions, which included cessation of nivolumab, administration of systemic corticosteroids, intravenous immunoglobulin therapy, a thrombopoietin receptor agonist, platelet transfusion, and rituximab treatment, resulted in 82.4% of subjects achieving normalized platelet counts, whereas 5.9% passed away due to ITP. ITP is a rare life-threatening immune-related adverse event and necessitates close monitoring. Systemic steroids are the primary treatment for ITP, while intravenous immunoglobulin, thrombopoietin receptor agonist and rituximab are other options.

Drug-induced thrombocytopenia associated with trastuzumab in a patient with HER2-positive recurrent gastric cancer

Here, we report a 57-year-old female patient with HER2-positive recurrent gastric cancer who experienced drug-induced thrombocytopenia associated with trastuzumab, a humanized anti-HER2 monoclonal antibody. Shortly after the initiation of S-1, oxaliplatin, and trastuzumab chemotherapy, the patient experienced severe thrombocytopenia and did not respond to platelet transfusions. Based on the findings of increased numbers of polynuclear megakaryocytes in the bone marrow and an elevated level of platelet-associated IgG (PA-IgG), the patient was diagnosed with drug-induced thrombocytopenia (DITP). The platelet count recovered rapidly with oral prednisolone (1 mg/kg). Since we initially suspected oxaliplatin as the causal agent, S-1 was restarted as a monotherapy, followed by trastuzumab after a 3-week interval, without oxaliplatin. On the second day after the addition of trastuzumab, severe thrombocytopenia occurred again, which suggests that trastuzumab was responsible for the DITP. The patient no longer experienced severe thrombocytopenia during the subsequent S-1 and oxaliplatin chemotherapy, which supports this hypothesis.

A Case of Multiple Cerebral Infarction Preceding Acute Exacerbation of Idiopathic Thrombocytopenic Purpura

BackgroundAlthough it was suggested that idiopathic thromobocytopenic purpura (ITP) can be a paradoxical cause of cerebral infarction, previous reports indicate that cerebral infarction associated with ITP occurs when thrombocytopenia is already evident at the onset of cerebral infarction. Case reportWe report a case of multiple cerebral infarction that preceded acute exacerbation of ITP. An 80-year-old woman with a history of ITP presented with tetraplegia, and brain magnetic resonance imaging revealed multiple infarction in bilateral cerebral and cerebellar hemispheres. For ITP, she was treated with oral prednisolone and subcutaneous injection of thrombopoietin receptor agonists. Her platelet count was within the normal range at the onset of cerebral infarction. Medical work-up did not reveal the obvious causes of her multiple cerebral infarction. On day 10 of hospitalization, she showed melena and oral hemorrhage and her platelet count markedly decreased. Her platelet-associated IgG level was elevated and a diagnosis of acute exacerbation of ITP was made. She was treated with intravenous immunoglobulin and her platelet count increased moderately. However, her neurological symptoms and cerebral infarction on magnetic resonance imaging deteriorated accompanied by hemorrhagic transformation. Finally, she died of respiratory failure. ConclusionsOur case suggests that thrombophilia accompanied by ITP can precede actual exacerbation of ITP and we have to consider ITP as a possible cause of multiple cerebral infarction, even when the platelet count is within the normal range at the onset of cerebral infarction.

Critical role of CD4+CD25+ regulatory T cells in preventing murine autoantibody-mediated thrombocytopenia

Autoimmune response suppression by regulatory T cells (Tregs) helps to maintain peripheral immune tolerance, and defects in this mechanism are thought to play a role in the pathogenesis of various autoimmune diseases. In patients with immune thrombocytopenia, naturally occurring CD4(+)CD25(+) Tregs are both functionally impaired and reduced in number. Thisstudy was undertaken to investigate Tregs' role in preventing immune thrombocytopenia in mice. Treg-deficient mice were prepared by inoculation of Treg-depleted CD4(+)CD25(-) Tcells isolated from BALB/c mice into syngeneic nude mice intravenously. Platelet count, proportion of reticulated platelets, platelet-associated IgG, platelet-associated anti-platelet antibodies, and IgG anti-platelet antibody production in splenocyte cultures were examined by flow cytometry. Of 69 Treg-deficient mice, 25 (36%) spontaneously developed thrombocytopenia that lasted at least 5 weeks. The platelet-associated IgG level and proportion of reticulated platelets were elevated in the thrombocytopenic mice. Platelet eluates and splenocyte culture supernatants prepared from thrombocytopenic mice, but not from nonthrombocytopenic mice, contained IgG antibodies capable of binding to intact platelets. Simultaneous transfer of Tregs completely prevented the onset of thrombocytopenia, but Treg transfer after the onset of thrombocytopenia had no apparent effect. Treatment with IgG anti-cytotoxic Tlymphocyte-associated antigen 4 antibody canceled this Treg-governed suppressive effect.In summary, these results indicate that Tregs play a critical role in preventing murine autoantibody-mediated thrombocytopenia by engaging cytotoxic T lymphocyte-associated antigen4.

Pathway of Toll-Like Receptor 7/B Cell Activating Factor/B Cell Activating Factor Receptor Plays a Role in Immune Thrombocytopenia In Vivo

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by anti-platelet autoantibody-mediated platelet destruction. Antigen-presenting cell (APC) dysfunction is considered to play crucial roles in ITP. However, how APC affects autoreactive B cells in ITP is still unknown. Using a mouse model of immune thrombocytopenia, we demonstrated an increase in levels of TLR7 in splenic mononuclear cells (SMCs). Using both TLR7 agonist and TLR7 silencing lentivirus, we found stimulation of TLR7 decreased platelet counts and increased levels of platelet-associated IgG (PAIgG) in ITP mice, which correlates TLR7 with platelet destruction by autoantibodies. Levels of serum BAFF increased significantly in ITP mice and stimulation of TLR7 promoted secretion of BAFF. Among the three BAFF receptors, only BAFF receptor (BAFF-R) increased in ITP mice. However, activation of TLR7 showed no effect on the expression of BAFF receptors. These findings indicate that upregulation of TLR7 may augment BAFF secretion by APC and through ligation of BAFF-R promote autoreactive B cell survival and thus anti-platelet autoantibody production. The pathway of TLR7/BAFF/BAFF-R provides us with an explanation of how activation of APC affects autoantibody production by B cells in ITP and thus might provide a reasonable therapeutic strategy for ITP.

Angioimmunoblastic T-cell lymphoma with autoimmune thrombocytopenia: A report of two cases

We report two patients, a 68-year-old man (Case 1) and a 66-year-old man (Case 2), with polyclonal gammopathy, lymphadenopathy, thrombocytopenia, and high platelet-associated IgG (PAIgG) level. We initially diagnosed them as having angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). From confirmation of clear cells by careful observation and detection of rearrangement bands of T cell receptors by Southern blot hybridization analysis, we finally concluded that their diagnoses were compatible with angioimmunoblastic T-cell lymphoma (AILT). AILT with autoimmune thrombocytopenia (AIT) is very rare, and all the reported cases were Japanese ones.

Increased Phagocytosis of Platelets from Patients with Secondary Dengue Virus Infection by Human Macrophages

The relationship between the percent phagocytosis of platelets by differentiated THP-1 cells was examined using flowcytometry and the peripheral platelet counts as well as platelet-associated IgG (PAIgG) in 36 patients with secondary dengue virus (DV) infections. The percent phagocytosis and the levels of PAIgG were significantly increased in these patients during the acute phase compared with the healthy volunteers. The increased percent phagocytosis and PAIgG found during the acute phase significantly decreased during the convalescent phase. An inverse correlation between platelet count and the percent phagocytosis (P = 0.011) and the levels of PAIgG (P = 0.041) was found among these patients during the acute phase. No correlation was found, however, between the percent phagocytosis and the levels of PAIgG. Our present data suggest that accelerated platelet phagocytosis occurs during the acute phase of secondary DV infections, and it is one of the mechanisms of thrombocytopenia in this disease.

Mechanisms of thrombocytopenia in patients with lymphoproliferative diseases.

Different factors are involved in the development of thrombocytopenia in patients with lymphoproliferative disorders. Significant correlation was detected between the number of megakaryocytes in bone marrow and platelet count (r = 0.485, p = 0.002, n = 37) and significant difference between the number of megakaryocyte in patients with normal platelet count (> 200,000/microliters) and patients with marked thrombocytopenia (platelet count < 100,000/microliters). All patients in the latter group (n = 15) had a relatively low number of megakaryocytes. Low but significant reverse correlation was found between the level of platelet-associated IgG (PA-IgG) and platelet count (r = -0.249, p = 0.024, n = 82) and significant difference between the mean levels of PA-IgG in the groups of patients with platelet count > 200,000/microliters and < 100,000/microliters. PA-IgG were increased in 46% of patients in the total group and in 65% of patients with platelet count < 100,000/microliters. The correlation between platelet count and PA-IgG was about 2 times higher in splenectomized (r = -0.549, p = 0.005, n = 24) than nonsplenectomized patients. All splenectomized patients with platelet count < 100,000/microliters (n = 8) had a significant increase in PA-IgG. Serum antibodies were detected in only 7% of tested patients. This group was characterized by severe thrombocytopenia (in 6 of 10 patients--platelet count < 50,000/microliters) and a high incidence of haemorrhages (in 5 of 10 patients). Thus the depression of platelet production was suggested to be the basic cause of thrombocytopenia in lymphoproliferative disorders. Involvement of immune mechanisms was revealed in a large number of patients and correlated with a deeper and more complicated thrombocytopenia.

Platelet associated IgG and immune thrombocytopenia in lymphoproliferative and autoimmune disorders.

Thrombocytopenia is frequently encountered in patients with lymphoproliferative disorders (LPD) and systemic erythromatosus (SLE) and to a lesser extent in association with other diseases such as rheumatoid arthritis (RA), pernicious anaemia (PA) and autoimmune haemolytic anaemia (AIHA). This report attempts to document the incidence of thrombocytopenia in these disorders, other than that overtly due to malignant infiltration or marrow suppression by drugs and to demonstrate, that in a significant proportion antibody mediated immune destruction of platelets can be confirmed by positive platelet antibody tests. Platelet associated IgG (PAIgG) was measured in all patients by a quantitative enzyme linked assay. Platelet antibodies were found in 11 of 24 (46%) thrombocytopenic patients with LPD, 10 of 16 (62%) patients with SLE and thrombocytopenia, and in all patients with RA and PA who had low platelet counts at the time of study. In addition, elevated PAIgG levels were found in the following non-thrombocytopenic patients: 9 of 43 (21%) patients with LPD, 2 of 12 (17%) with SLE, 2 of 12 (17%) with AIHA, 2 of 39 (5%) with PA and 5 of 61 (8%) patients with RA. The nature and the role of raised PAIgG levels in diseases other than autoimmune thrombocytopenia is controversial. Our reasons for interpreting these as true platelet autoantibodies in this selected group of disorders and the clinical implications of our results are discussed.

A double antibody radioassay for the detection of platelet associated IgG.

A double antibody radioimmunoassay has been developed for the detection of platelet associated IgG (PAIgG). The assay employs conventional radioassay technology and, as such, readily may be adopted by laboratories familiar with radioassay techniques. The assay is sensitive to 0.6 ng IgG and can be undertaken on 10(6)-10(7) platelets, or fewer in the case of thrombocytopenia with raised PAIgG. The assay can be completed within 2 working days. Normal PAIgG levels in EDTA blood were 0.8 to 5.7 micrograms IgG/10(9) platelets. However, normal levels depended upon the anticoagulant used for blood collection and were on average five-fold higher for blood taken into EDTA than for blood taken into ACD; normal range 0.1-1.2 micrograms/IgG 10(9) platelets. PAIgG was assayed on blood taken simultaneously into ACD and EDTA from 15 patients with chronic idiopathic thrombocytopenia (ITP). PAIgG was raised in 14 out of 15 EDTA samples, but in only 11 of 15 ACD samples. EDTA was therefore regarded as the anticoagulant of choice. A total of 20 of 23 (87%) patients with chronic ITP had PAIgG values above the normal range. The PAIgG in chronic ITP was weakly related to platelet count, weakly and inversely related to platelet volume, but was independent of serum IgG concentration.

The effect of storage in different anticoagulants on platelet associated IgG.

Blood was collected from nine normal volunteers into each of four different anticoagulants and in order to simulate transport conditions, was stored at room temperature for 96 h. The platelet associated IgG (PAIgG) was determined from aliquots thereof over this period. Blood in EDTA gave slightly higher initial values (day 0) than in other anticoagulants. PAIgG levels increased at different rates in all anticoagulants thereafter. In contrast to recent reports which suggested that falsely elevated levels were likely to be seen after storage in EDTA, we found little difference in these values in blood in different anticoagulants at 72 h and all PAIgG measurements remained within our quoted normal range at this time. After 96 h storage however, one of nine (11%) in CPD-A, two of nine (22%) in EDTA, two of nine (22%) in Na-citrate and six of nine (66%) in EDTA paraformaldehyde gave falsely elevated results. The possible mechanisms of these changes are discussed. The assay system employed in this study measures 'total' platelet IgG in a platelet extract in contrast to some other assays which quantify surface platelet IgG alone and it is possible that this difference in technique is responsible for the relatively smaller percentage changes after storage than reported by others. All anticoagulants tested in this study proved satisfactory both for handling and for the measurement of PAIgG at 48 h, with the proviso that normal ranges should be established for each.

Danazol treatment of myelodysplastic syndromes

Peripheral cytopenias are common in patients with myelodysplastic syndromes. We previously successfully treated three such patients with improvement of some cytopenias with the impeded androgen danazol. To confirm this finding and elucidate the mechanism of response, we treated an additional 22 patients with myelodysplasia with oral danazol (600-800 mg daily) for 3-12 months. Eleven of 22 evaluable patients taking danazol met our criteria for improvement of peripheral counts, mainly thrombocytopenia. Chromosome analysis, marrow culture studies and serial bone marrow biopsies revealed no alteration of the abnormal clone or normal haematopoiesis in patients on danazol therapy. This suggested that improvement in blood counts was not related to modulation of ineffective haematopoiesis. Investigation of the thrombocytopenia in these patients revealed that most patients presented with markedly elevated platelet associated IgG (PAIgG), elevated plasma platelet-bindable IgG (PBIgG), and an elevated number of monocyte Fc gamma receptors. Treatment with danazol was associated with a decline in monocyte Fc gamma receptor number without significantly altering the elevated PAIgG or PBIgG levels. These results are similar to our observations in patients treated with danazol for chronic idiopathic thrombocytopenia purpura (ITP). Our data suggest that a component of the thrombocytopenia occurring in patients with myelodysplasia may be due to enhanced peripheral blood cell destruction by abnormal macrophages. Danazol may modulate cytopenia by decreasing the number of monocyte Fc gamma receptors. Danazol treatment was associated with minimal toxicity, but clinically meaningful responses were rare.

Lack of Efficacy of High-Dose Intravenous Immunoglobulin Treatment of Severe Thrombocytopenia in Patients with Secondary Dengue Virus Infection

Because most cases of secondary dengue virus infection are associated with an increased level of platelet-associated IgG, a high dose of intravenous immunoglobulin (IVIG) may have an effect on the development of severe thrombocytopenia in this disease. A randomized, controlled study was conducted with two treatment groups consisting of a treatment (IVIG) group (n = 15) and a non-treatment (non-IVIG) group (n = 16) to determine whether a high dose of IVIG is effective in hastening the recovery from thrombocytopenia in patients with secondary dengue virus infection. No significant difference was found in the baseline demographic data between the two groups. No adverse effect of IVIG was observed, but no effect in hastening the recovery of platelet counts was found in patients with secondary dengue infections. The lack of efficacy of IVIG suggests that platelet clearance by macrophages through Fc gamma receptors is not a primary mechanism in this disease.

Acute myelogenous leukemia with multilineage myelodysplasia, positive direct Coombs test, and elevated levels of platelet-associated IgG

Acute myelogenous leukemia with multilineage myelodysplasia, positive direct Coombs test, and elevated levels of platelet-associated IgG

Immune Thrombocytopenic Purpura Associated with Pulmonary Tuberculosis

A 22-year-old woman was admitted into our hospital because of generalized purpura and abnormalities in her chest X-ray. Isolated thrombocytopenia and elevated platelet-associated IgG levels were detected, while the bone marrow examination was normal. Mycobacterium tuberculosis was detected in the bronchoalveolar lavage fluid, and consequently she was diagnosed as having active tuberculosis. High-dose immunoglobulin therapy combined with anti-tuberculosis drugs not only rapidly and continuously corrected thrombocytopenia but also cured pulmonary tuberculosis. This case suggests a causal association between immune thrombocytopenia and tuberculosis as well as the safety and efficacy of the anti-tuberculosis drugs combined with high-dose immunoglobulin therapy.

Association of increased platelet-associated immunoglobulins with thrombocytopenia and the severity of disease in secondary dengue virus infections

Severe thrombocytopenia and increased vascular permeability are two major characteristics of dengue haemorrhagic fever (DHF). To develop a better understanding of the roles of platelet-associated IgG (PAIgG) and IgM (PAIgM) in inducing thrombocytopenia and its severity of disease in patients with secondary dengue virus infection, the relationship between the PAIgG or PAIgM levels and disease severity as well as thrombocytopenia was examined in 78 patients with acute phase secondary infection in a prospective hospital-based study. The decrease in platelet count during the acute phase recovered significantly during the convalescent phase. In contrast, the increased levels of PAIgG or PAIgM that occurred during the acute phase of these patients decreased significantly during the convalescent phase. An inverse correlation between platelet count and PAIgG or PAIgM levels was found in these patients. Anti-dengue virus IgG and IgM activity was found in platelet eluates from 10 patients in an acute phase of secondary infection. Increased levels of PAIgG or PAIgM were significantly higher in DHF than those in dengue fever (DF). An increased level of PAIgM was associated independently with the development of DHF, representing a possible predictor of DHF with a high specificity. Our present data suggest that platelet-associated immunoglobulins involving antidengue virus activity play a pivotal role in the induction of thrombocytopenia and the severity of the disease in secondary dengue virus infections.

Intravenous cyclophosphamide therapy in a case with refractory thrombotic microangiopathic hemolytic anemia and SLE

The case of a 27-year-old woman who simultaneously presented with SLE and severe refractory thrombotic microangiopathic hemolytic anemia (TMHA) is reported. She had extremely high levels of platelet-associated IgG (PAIgG), and her TMHA was refractory to plasma exchange and corticosteroid therapy. However, the TMHA was effectively controlled by i.v. cyclophosphamide therapy. ITP and TTP are generally considered distinct diseases; however, TMHA may occur secondary to platelet aggregation via autoimmune mechanisms in certain cases. Immunosuppressive therapy at an early stage of the disease may be beneficial in refractory cases of TMHA with autoimmune features.

Serum leptin levels in patients with idiopathic thrombocytopenic purpura.

The purpose of this study was to evaluate serum leptin levels in idiopathic thrombocytopenic purpura (ITP), in order to determine the influence of leptin on the pathogenesis of ITP. Forty-six untreated patients with chronic ITP were compared with 40 healthy people of similar age, sex and body mass index (BMI). Serum leptin levels (ng/mL) were measured by enzyme-linked immunosorbent assay (ELISA). We found that the mean serum leptin levels in patients with ITP (22.11 +/- 15.84 ng/mL) were significantly (P < 0.001) higher than that in healthy control volunteers (5.44 +/- 4.84 ng/mL). Furthermore, serum leptin levels in patients with ITP were inversely related (r = -0.86, P < 0.001) to the platelet counts and positively related to the platelet-associated IgG (PAIgG) levels (r = 0.7, P < 0.001). The levels of PAIgG and platelet counts were significantly different between leptin-positive (level greater than mean +/- 2 SD control value) and leptin-negative patients. These findings suggest that leptin might play an important role in the pathogenesis of ITP.

Correlation between increased platelet-associated IgG and thrombocytopenia in secondary dengue virus infections.

Although the public health impact of dengue is increasing rapidly, the mechanism of thrombocytopenia in this disease remains unknown. To elucidate this mechanism, the relationship between platelet-associated IgG (PAIgG) and platelet count in 53 patients in the acute phase of secondary dengue virus infection was investigated in a prospective-hospital-based study. A significant inverse correlation between the two parameters was found in these patients, while no correlation was observed in healthy volunteers. The low baseline platelet counts during the acute phase in 12 patients with secondary dengue virus infection significantly increased during the convalescent phase, while the increased PAIgG levels during the acute phase in these patients significantly decreased during the convalescent phase. Anti-platelet IgG autoantibody was detected rarely in the plasma of 53 patients with secondary dengue infection. The involvement of anti-dengue virus IgG was also shown in platelets from all of 8 patients in the acute phase of secondary dengue virus infection. These findings suggest that PAIgG formation involving anti-dengue virus IgG plays a pivotal role in the induction of transient thrombocytopenia during the acute phase of secondary dengue virus infection.

ASSOCIATION OF DENGUE VIRUS TYPE-SPECIFIC IGG ON PLATELETS IS SPECIFIC FOR THE ACUTE PHASE IN AN IMPORTED JAPANESE PATIENT WITH SECONDARY DENGUE 2 VIRUS INFECTION

The mechanism of thrombocytopenia in dengue virus infection remains unknown. We report herein an imported case of a 21-year-old male Japanese with dengue fever caused by secondary dengue 2 virus infection. The thrombocytopenia detected around the day of defervescence was associated with an increased level of platelet-associated IgG (PAIgG). The eluate from the platelets during the acute phase of this case contained an increased activity of anti-dengue virus 2 IgG, while the eluate from platelets during the convalescent phase contained a low level of anti-dengue 2 IgG. These findings suggest the transient formation of PAIgG involving anti-dengue 2 virus IgG during the acute phase of secondary dengue 2 virus infection.