Immune-mediated Thrombocytopenia Research Articles

#2672 Cryoglobulin-Induced membranoproliferative glomerulonephritis in a HEV-infected kidney transplant recipient: outcomes post ribavirin failure

Abstract Background and Aims Hepatitis E is a zoonosis caused by hepatitis E virus (HEV), which was first discovered 40 years ago. It is the most prevalent hepatitis virus worldwide. Most hepatitis E cases are self-limiting acute hepatitis, but the virus has been recognized to cause chronic hepatitis. Following the first case report of chronic hepatitis E (CHE) in a transplant recipient, CHE has recently been identified as associated with chronic liver damage induced in immunocompromised patients such as transplant recipients. CHE can induce extra-hepatic manifestations, such as immune-mediated thrombocytopenia, neurological symptoms, and kidney injuries. Few cases of glomerulonephritis (GN) and cryoglobulinemia in transplant patients have been related with CHE, with a good progression thanks to viral control with ribavirin introduction. There have been no reported cases in the literature of good progress in renal function in renal transplant patients despite failure of treatment with Ribavirin. Method We report here what is to our knowledge, the first documented case of HEV-induced de novo cryoglobulinemic membranoproliferative glomerulonephritis in a renal transplant patient with a ten-year history of CHE infection unsuccessfully treated with ribavirin. Results A 69-year-old man underwent a kidney transplant for diabetes type 1. 7 years after transplantation, he was diagnosed with a chronic genotype 3.1H-HEV infection. He was treated by Ribavirin, but it did not allow to eradicate HEV but a biochemical response. At 18 years post transplant, he presented with asthenia, abdominal pains and increased liver enzyme levels: liver tests were disrupted with cytolysis and cholestasis. He presented also a nephritic syndrome with high blood pressure, oedemas, increased serum creatinine level, proteinuria with hypoalbuminemia and de novo microscopic hematuria. Biological analysis revealed presence of type 2 cryoglobulinemia with monoclonal IgM Kappa (2285 mg/L), and polyclonal immunoglobulins association. Rheumatoid factor was increased (573 UI/ml) and C4 level was reduced (0.04 g/L). The concentration of HEV RNA in the serum was 750 000 UI/mL. Viral serologies were performed for HBV, HCV, HAV, HIV, EBV, CMV. Hematologic diseases were ruled out by analyzing a bone marrow biopsy specimen. Histologic analysis of a kidney biopsy specimen revealed diffuse endocapillary proliferation, diffuse mesangial proliferation and focal glomerular basal membrane duplication. One arteriolar section showed a focal lesion of vasculitis (Fig. 1). There was no argument for allograft rejection. Immunofluorescence microscopy revealed mesangial and capillary wall deposits of IgM, IgG, C3 and C1q, polytypic for k and l light chains. We suspected cryoglobulinemic membranoproliferative glomerulonephritis induced by VHE. The initial treatment plan involved 10 sessions of plasmapheresis and steroid pulses (500 mg/d for 3 days), alongside a course of rituximab (1 g/week for 4 weeks). However, the patient experienced intolerance to rituximab, prompting a switch to Obinutuzumab. Subsequently, the anti-HEV therapy was modified, and the patient was placed on a course of Sofosbuvir. Consequently, three months after treatment kidney function kidney improved with return to baseline and cryoglobulinemia became undetectable. However, proteinuria remained impaired and VHE RNA was still present. Conclusion Cryoglobulinemia is rarely associated with glomerular disease in HEV infection, and cases currently reported in the literature showed a favorable outcome with ribavirin. This case is the first to display a chronic HEV infection with cryoglobulin-induced glomerulonephritis with global improvement despite unsuccessful treatment with ribavirin. Although the difficulty of managing immunity in the treatment of cryoglobulinemia by immunodepleting treatment, with the risk of increased viral replication in the absence of an effective antiviral, it seems interesting to offer a first-line treatment of cryoglobulinemia that appears to improve renal function despite continued viral replication. These results need to be confirmed in further studies.

Platelet-derived TGF-β1 induces functional reprogramming of myeloid–derived suppressor cells in immune thrombocytopenia

AbstractPlatelet α-granules are rich in transforming growth factor β1 (TGF-β1), which is associated with myeloid–derived suppressor cell (MDSC) biology. Responders to thrombopoietin receptor agonists (TPO-RAs) revealed a parallel increase in the number of both platelets and MDSCs. Here, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to establish an active murine model of immune thrombocytopenia (ITP). Subsequently, we demonstrated that TPO-RAs augmented the inhibitory activities of MDSCs by arresting plasma cells differentiation, reducing Fas ligand expression on cytotoxic T cells, and rebalancing T-cell subsets. Mechanistically, transcriptome analysis confirmed the participation of TGF-β/Smad pathways in TPO-RA–corrected MDSCs, which was offset by Smad2/3 knockdown. In platelet TGF-β1–deficient mice, TPO-RA-induced amplification and enhanced suppressive capacity of MDSCs was waived. Furthermore, our retrospective data revealed that patients with ITP achieving complete platelet response showed superior long-term outcomes compared with those who only reach partial response. In conclusion, we demonstrate that platelet TGF-β1 induces the expansion and functional reprogramming of MDSCs via the TGF-β/Smad pathway. These data indicate that platelet recovery not only serves as an end point of treatment response but also paves the way for immune homeostasis in immune-mediated thrombocytopenia.

Autoimmune complexity: A case report of immune thrombocytopenia (ITP) with coexistent positive autoimmune markers and multidisciplinary challenges

This case study explores a complex clinical presentation of an 85-year-old male diagnosed with immune-mediated thrombocytopenia (ITP) with coexistent positive autoimmune markers. A multidisciplinary approach was crucial in managing the patient, involving hematology, rheumatology, urology, and respiratory specialists. Despite tailored treatments, including platelet transfusions, immunosuppressive therapies, and antibiotics, the patient developed complications including hospital-acquired pneumonia, pulmonary infection, and acute kidney injury. Extensive discussions with the family led to the decision to transition the patient to comfort care, emphasizing the challenges in managing complex cases and the importance of a comprehensive care plan.

Retrospective evaluation of leflunomide as an adjunctive therapy in dogs with non-associative immune-mediated thrombocytopenia: 20 cases (2008-2021).

To describe leflunomide as an adjunctive therapy in the treatment of non-associative immune-mediated thrombocytopenia. A retrospective study of dogs with a diagnosis of non-associative immune-mediated thrombocytopenia treated with leflunomide March 2008 to September 2021 was conducted. Data collected included signalment, clinical signs, physical examination findings and diagnostic testing performed. Medications administered, duration of hospital stay, time to platelet concentration >150×109/L and adverse events during leflunomide therapy were recorded. Relapses within a year of diagnosis were reported. A total of 20 client-owned dogs met inclusion criteria. Nineteen of 20 dogs (95%) achieved a platelet concentration >150×109/L with leflunomide and prednisone combination therapy and four dogs (21.1%) relapsed during treatment or shortly after treatment. Adverse effects included diarrhoea (n=5), mild lymphopenia (n=9) and mild intermittent anaemia (n=1). A single dog developed hepatotoxicity presumed to be secondary to leflunomide therapy that resolved after drug discontinuation. One dog was treated for aspiration pneumonia during treatment. Two dogs were euthanased while receiving leflunomide. Length of hospitalisation, time to platelet recovery, treatment response and relapse rate were comparable with alternative treatment protocols. Most adverse effects did not require leflunomide dose adjustment; however, two dogs died while undergoing leflunomide treatment and there is compelling evidence that one of these dogs experienced fatal infection secondary to immune-suppression. Hepatotoxicity remains a known complication of leflunomide treatment and serial biochemistry testing is recommended.

CASE REPORT: INHERITED MACROTHROMBOCYTOPENIA IN A CAVALIER KING CHARLES SPANIEL

A 11-month-old intact male Cavalier King Charles Spaniel (CKCS) dog was presented at the Teaching Hospital of National Chung Hsin University (NCHU-VMTH) due to thrombocytopenia without relevant clinical signs and no significant improvement after medication treatment. As per the complete blood profile, there was significant thrombocytopenia (platelet count 1–[Formula: see text] L) with mean platelet volume (MPV) ranging from 20.3 to 25.7[Formula: see text]fl. Tests for Babesia canis, B. gibsoni, Ehrlichia canis and Anaplasma phagocytophilum yielded negative results. Despite treatment with antibiotics and immunosuppressive drugs, the dog’s condition did not improve. The dog’s platelet morphology and absence of symptoms raised the suspicion of inherited macrothrombocytopenia. Genomic DNA sequencing analysis of the [Formula: see text]1-tubulin gene revealed a single-point mutation, specifically c.745[Formula: see text]G>A. This genetic analysis confirmed the presence of a [Formula: see text]1-tubulin mutation, marking the first reported case of such a mutation in a CKCS in Taiwan. Despite the diagnosis of this condition, both partial thromboplastin time (PTT) and active partial thromboplastin time (aPTT) were within normal ranges before neutering. When diagnosing the causes of thrombocytopenia in young patients, especially when there are no related clinical signs, it is crucial to consider prioritizing inherited macrothrombocytopenia, then thrombocytopenia secondary to parasite infection, or immune-mediated thrombocytopenia (IMT) to minimize unnecessary medication.

Comparison of timing of relapse in dogs with nonassociative immune-mediated hemolytic anemia, thrombocytopenia, or polyarthritis.

Relapse is a clinical concern in dogs diagnosed with immune-mediated hemolytic anemia (IMHA), thrombocytopenia (ITP), or polyarthritis (IMPA). The average time to relapse is unknown, and evidence that vaccination is associated with disease relapse is lacking. Compare the incidence of relapse in groups of dogs with IMHA, ITP, or IMPA over a 24-month period after diagnosis and compare proportions of dogs that received vaccines in those dogs that did and did not relapse. One hundred sixty client-owned dogs (73 with IMHA, 55 with ITP, 32 with IMPA). Medical records of dogs were reviewed with the goal of following cases for a minimum of 2 years. Incidence of relapse was calculated for each disease, and relapse rates in dogs that were or were not vaccinated after diagnosis were compared. Relapse rates at 12 months differed significantly among disease groups (P = .02), with a higher rate for IMPA (35%) compared to IMHA (11%) or ITP (11%). Relapse rate at 24 months was 41% for IMPA, 18% for IMHA, and 23% for ITP. Ninety percent of IMPA relapses occurred in the first 12 months after diagnosis, compared with 56% for IMHA and 50% for ITP. Vaccine administration after diagnosis was not associated with relapse (P = .78). Risk of disease relapse in IMPA is highest in the first year after diagnosis, with a higher relapse rate compared with IMHA and ITP. The role of vaccination in disease relapse remains unclear.

Use of human intravenous immunoglobulin for the treatment of 12 dogs with newly diagnosed malignant disease and presumed secondary immune-mediated thrombocytopenia.

To evaluate the safety and efficacy of human intravenous immunoglobulin in dogs with newly diagnosed malignancy and presumed secondary immune-mediated thrombocytopenia. Twelve client-owned dogs with newly diagnosed malignant disease and presumed secondary immune-mediated thrombocytopenia were prospectively enrolled to receive a single infusion of human intravenous immunoglobulin at a dose of 0.5 to 1 mg/kg intravenous over 8 hours. A complete treatment response was defined as a platelet estimation of ≥40,000 platelets/μL within 24 hours and a partial response within 48 hours from the completion of human intravenous immunoglobulin infusion. No treatment response was defined as a platelet estimation remaining <40,000 platelets/μL over 48 hours from the completion of the human intravenous immunoglobulin infusion. This pilot study had a prospective, open-label, uncontrolled design. Out of the 12 enrolled dogs, seven completed the study. A complete treatment response to human intravenous immunoglobulin was identified in one lymphoma dog and a partial response was noted in another lymphoma dog. The remaining 10 dogs had no response to human intravenous immunoglobulin. No clinically relevant adverse reactions to human intravenous immunoglobulin occurred in any of the 12 initially enrolled dogs during the infusion and over a 3-month follow-up period for the seven surviving dogs. The results of this study suggest that the use of human intravenous immunoglobulin in dogs with newly diagnosed malignant disease and presumed secondary immune-mediated thrombocytopenia appears safe, but not effective for the treatment of thrombocytopenia. Larger multi-centre, prospective, double-blinded, placebo-controlled, outcome-based, malignancy-specific studies are needed to further evaluate these preliminary findings.

Immune-mediated thrombocytopenia and IL-6-mediated thrombocytosis observed in idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare haematological disorder characterized by generalized lymphadenopathy with atypical histopathological features and systemic inflammation caused by a cytokine storm involving interleukin-6 (IL-6). Three clinical subtypes are recognized: thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly (iMCD-TAFRO); idiopathic plasmacytic lymphadenopathy (iMCD-IPL), involving thrombocytosis and hypergammaglobulinaemia; and iMCD-not otherwise specified (iMCD-NOS), which includes patients who do not meet criteria for the other subtypes. Disease pathogenesis is poorly understood, with potential involvement of infectious, clonal and/or autoimmune mechanisms. To better characterize iMCD clinicopathology and gain mechanistic insights into iMCD, we analysed complete blood counts, other clinical laboratory values and blood smear morphology among 63 iMCD patients grouped by clinical subtype. Patients with iMCD-TAFRO had large platelets, clinical severity associated with lower platelet counts and transfusion-resistant thrombocytopenia, similar to what is observed with immune-mediated destruction of platelets in immune thrombocytopenic purpura. Conversely, elevated platelet counts in iMCD-IPL were associated with elevated IL-6 and declined following anti-IL-6 therapy. Our data suggest that autoimmune mechanisms contribute to the thrombocytopenia in at least a portion of iMCD-TAFRO patients whereas IL-6 drives thrombocytosis in iMCD-IPL, and these mechanisms likely contribute to disease pathogenesis.

High Frequency of Genetic Variants Influencing Diagnosis and Bleeding Pattern in Patients with Presumed Primary Immune Mediated Thrombocytopenia (ITP)

Introduction Immune mediated thrombocytopenia (ITP) is a platelet disorder in which the immune system attacks and destroys the body's own platelets. Mechanisms leading to low platelet count in ITP are multifactorial, involving both increased peripheral platelet destruction and decreased platelet production. This is caused by autoantibodies targeting megakaryocytes and platelet-specific glycoproteins, as well as cytotoxic T cells directly acting on platelets. Although antibodies in some cases can be found in patients with ITP, there is no well-established diagnostic test and the diagnosis is thus, one of exclusion. While most cases of ITP resolve within 3 months with or without treatment, some patients do not respond to conventional treatment and develop a refractory ITP. It is likely that in the group of patients diagnosed with refractory ITP, some does not have an immune mediated thrombocytopenia, but other causes of low counts (PLC)s. With the development of high throughput sequencing and the increasing knowledge of inherited bleeding disorders, the possibility to identify the underlying cause of disease in these patients is steadily growing. In ITP, there is a high degree of interindividual differences in bleeding rates, where some patients have no bleeding symptoms despite of unmeasurable PLC, whereas other patients show severe bleeding symptoms at PLC &amp;gt; 30 x10 9 /L. The underlying etiology of these discrepancies is currently unknown and complicates the clinical care of these patients. We hypothesize that genetic defects influence the bleeding pattern in true ITP patients as well as being one of the underlying causes of thrombocytopenia in patients misdiagnosed with “refractory ITP”. The aim of this pilot study was to investigate whether upfront genetic screening of patients suspected of ITP could be a valuable diagnostic tool to determine presence of inherited thrombocytopenia, secondary thrombocytopenia and genetic variants that might affect bleeding pattern. Method Patients were included after informed consent following the declaration of Helsinki. We performed whole genome sequencing (WGS) in patients diagnosed with presumed ITP at the Skåne University Hospital, Sweden. Whole genome sequencing was performed at the Center for Genomic Medicine at Rigshospitalet, Copenhagen. An in-silico gene panel consisting of 113 genes known to be associated with bleeding disorders as well as 86 genes associated with ITP (Using the VarSeq gene prioritisation algorithm phorank) was analysed and pathogenicity was classified according to the ACMG/AMP guidelines. Patients' medical records were examined, laboratory work up was performed and clinical data regarding demographics and information regarding bleeding was collected. A final evaluation of susceptible variants took place at multiple disciplinary team conferences. Results Twenty-one patients were enrolled (9 women, 12 men, 17 were adults and 4 children). Mean age of adult patients was 50,5 years and mean age of paediatric patients was 11,5 years. Out of 21 patients, 7 were shown to have genetic variants with relevance to their disease. All variants were found in adult patients. Two patients had variants related to inherited thrombocytopenia (X-linked thrombocytopenia(WAS) and monoallelic Bernard-Soulier Syndrome(GP1BB)), 4 had variants in genes related to secondary ITP (3 with variants associated with common variable immunodeficiency (NFKB1, TNFRSF13B) and 1 with systemic lupus erythematosus (TREX1)) and 1 had a variant associated with platelet dysfunction (platelet delta storage pool deficiency (UNC13D)). Only the variant associated with X-linked thrombocytopenia was previously described (class 5) whereas the remaining 6 variants were initially classified as variants of unknown significance (VUS). Functional work-up and co-segregation studies indicated them as probably pathogenic (class 4) but confirming studies are still pending. Conclusion In this pilot study, 33% of patients with presumed primary ITP had variants with relevance to their clinical phenotype, and we were able to diagnose 1 patient with an inherited bleeding disorder (X-linked thrombocytopenia). Whole genome sequencing seems to be a useful diagnostic tool in the work up of patients with thrombocytopenia where ITP is suspected to ensure the diagnosis and could also add important information when assessing bleeding risk in individual patients.

Platelet-Derived TGF-β1 Induces Functional Reprogramming of Myeloid-Derived Suppressor Cells in Immune Thrombocytopenia

Introduction: Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by isolated thrombocytopenia and varying degrees of bleeding symptoms. Platelets are anucleate cytoplasmic cell fragments that play dual physiological roles as both cellular mediators of thrombosis and immune modulatory cells. Platelets are the largest storage pool of TGF-β1, a crucial enforcer of immune homeostasis and tolerance. Studies have shown that TGF-β1 released by platelets contributes to the pathogenesis of pulmonary arterial hypertension and cervical carcinoma. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cells with potent immunosuppressive functions. Our previous studies have shown that MDSCs are impaired in number and function in patients with ITP. The objective of this study was to elucidate the underlying molecular mechanisms of MDSCs reprogramming by platelet-derived TGF-β1. Methods: A transwell assay was used to determine the impact of platelets on MDSCs induced from peripheral blood mononuclear cells (PBMCs) of ITP patients and healthy controls. The percentage of circulating MDSCs in ITP patients was detected before and after administration of thrombopoietin receptor agonists (TPO-RAs). Besides, anti-CD61 immune-sensitized splenocytes were transferred into SCID mice to establish an active murine model of ITP. Subsequently, MDSCs from TPO-RA-treated ITP mice were transplanted as cell therapy to rescue treatment-free ITP mice. In specific, adeno-associated viral (AAV) vectors efficiently infected MDSCs to enable cell-specific Smad2/3 knock-down. Finally, platelet specific TGF-β1-deficient mice were used to validate the effect of platelet-derived TGF-β1 on MDSCs. Results: TGF-β1 levels in the supernatant of MDSCs co-cultured with platelets of high concentration was significantly higher than that in MDSCs co-cultured with platelets of low concentration or alone. FACS analysis showed that platelet mass enhanced the inhibitory effects of MDSCs on the proliferation of CD4 + T cells, which could be offset by TGF-β1 inhibitor (TGF-βi). Besides, TPO-RAs treatment induced significantly increased percentage of circulating MDSCs in responders with chronic ITP. Likewise, TPO-RA significantly expanded MDSC population in active ITP murine models. Furthermore, after receiving donor MDSCs from TPO-RA-treated ITP mice, arrested differentiation of plasma cells, reduced Fas ligand expression on cytotoxic T cells, and re-balanced T cell subsets were found in the recipient mice, indicating augmented inhibitory functions of MDSCs. Mechanistically, transcriptome analysis confirmed the participation of TGF-β/Smad pathway in donor MDSCs from TPO-RA-treated ITP mice, which was offset by Smad2/3 knockdown. Finally, by constructing ITP models using Pf4 cre-Tgfb1 fl/fl and Pf4 cre+Tgfb1fl/fl mice, we found that TGF-β1 inhibition and platelet TGF-β1-deficence, both, could counteract the elevated platelet count and MDSCs percentage, as well as improved immunosuppressive capacity of MDSCs trigged by TPO-RA modulation. Conclusion: To sum up, it was demonstrated that platelet TGF-β1 induced the expansion and functional reprogramming of MDSCs via TGF-β/Smad pathway. These data indicate that platelet recovery not only serves as an endpoint of remission, but also paves the way for tolerance induction in immune-mediated thrombocytopenia. Our exploratory study deciphered immunological changes induced by TPO-RAs and helped to identify molecular mechanisms responsible for long-term remission after TPO-RA discontinuation.

Rifampicin induced acute thrombocytopenia with skin rashes: a case report

Rifampicin is an essential component of the treatment regimen for tuberculosis. Extensive clinical experience has shown that the drug has mild adverse effect, but on rare occasions, it can cause life threatening adverse reactions like thrombocytopenia. Blajchman et al first described rifampicin-induced thrombocytopenia in 1970. Since then, almost 40 cases have been documented in the literature and a recent review by Cooper and Ghanima included rifampicin in the group of not uncommon drugs that cause immune-mediated thrombocytopenia. Diagnosis of drug-induced immune thrombocytopenia is by identifying clinical symptoms and a careful evaluation of the suspected causative drug. The physician treating tuberculosis patients must be aware of this rare life-threatening complication, when we detected early, is completely reversible.

Immune-mediated hemolysis after administration of human intravenous immunoglobulin in a dog: a case report

A 10-year-old spayed female Maltese presented with purpura and hematemesis. Initial laboratory evaluation revealed immune-mediated thrombocytopenia, but evidence of hemolytic anemia was not identified. Three milligrams of human intravenous immunoglobulin (hIVIG) was administered for 3 hours following prednisolone and mycophenolate mofetil. A pale mucous membrane was identified, and the packed cell volume decreased by 3%. Blood film examination revealed significant spherocytosis with auto-agglutination. Blood transfusions and immunosuppression were continued for 4 days, and hIVIG was discontinued. This report describes a case of increased immune-mediated hemolysis after hIVIG administration, possibly due to new-onset immune-mediated hemolytic anemia or enhanced immunogenicity.

Refractory immune thrombocytopenia in adults: Towards a new definition.

Immune thrombocytopenia (ITP) is an autoimmune haematological disorder characterized by immune-mediated thrombocytopenia and a variable risk of bleeding. Despite the availability of multiple treatment options, some patients are considered refractory since they do not achieve a platelet count response to multiple treatments and are at risk of bleeding. The term 'refractory' has been used to identify this patient group; however, with the advent of multiple lines of treatment, its meaning has become ambiguous. To address this issue, we reviewed previous definitions of refractory ITP, solicited the views of ITP experts and collected data from registries to inform a definition. Twenty ITP experts who attended the 7th Expert Meeting of the Intercontinental Cooperative ITP Study Group in September 2022 answered a web-based survey: 95% felt that there was a need for a new definition of refractory ITP for clinical and research purposes. The use of the term refractory, accompanied by a clear indication of the type and timing of failed treatments, was supported by 85% of respondents. Preliminary data on the frequency of refractory patients from the McMaster and Norwegian ITP Registries demonstrated that the proportion of adult ITP patients who had failed first-line therapy, rituximab, thrombopoietin receptor agonists, any immune suppressant medication and splenectomy ranged from 0.4% to 3.8%. We propose a definition of refractory ITP that could be evaluated in future studies.

Risk of autoimmune diseases following COVID-19 and the potential protective effect from vaccination: a population-based cohort study

Case reports suggest that SARS-CoV-2 infection could lead to immune dysregulation and trigger autoimmunity while COVID-19 vaccination is effective against severe COVID-19 outcomes. We aim to examine the association between COVID-19 and development of autoimmune diseases (ADs), and the potential protective effect of COVID-19 vaccination on such an association. A retrospective cohort study was conducted in Hong Kong between 1 April 2020 and 15 November 2022. COVID-19 was confirmed by positive polymerase chain reaction or rapid antigen test. Cox proportional hazard regression with inverse probability of treatment weighting was applied to estimate the risk of incident ADs following COVID-19. COVID-19 vaccinated population was compared against COVID-19 unvaccinated population to examine the protective effect of COVID-19 vaccination on new ADs. The study included 1,028,721 COVID-19 and 3,168,467 non-COVID individuals. Compared with non-COVID controls, patients with COVID-19 presented an increased risk of developing pernicious anaemia [adjusted Hazard Ratio (aHR): 1.72; 95% Confidence Interval (CI): 1.12-2.64]; spondyloarthritis [aHR: 1.32 (95% CI: 1.03-1.69)]; rheumatoid arthritis [aHR: 1.29 (95% CI: 1.09-1.54)]; other autoimmune arthritis [aHR: 1.43 (95% CI: 1.33-1.54)]; psoriasis [aHR: 1.42 (95% CI: 1.13-1.78)]; pemphigoid [aHR: 2.39 (95% CI: 1.83-3.11)]; Graves' disease [aHR: 1.30 (95% CI: 1.10-1.54)]; anti-phospholipid antibody syndrome [aHR: 2.12 (95% CI: 1.47-3.05)]; immune mediated thrombocytopenia [aHR: 2.1 (95% CI: 1.82-2.43)]; multiple sclerosis [aHR: 2.66 (95% CI: 1.17-6.05)]; vasculitis [aHR: 1.46 (95% CI: 1.04-2.04)]. Among COVID-19 patients, completion of two doses of COVID-19 vaccine shows a decreased risk of pemphigoid, Graves' disease, anti-phospholipid antibody syndrome, immune-mediated thrombocytopenia, systemic lupus erythematosus and other autoimmune arthritis. Our findings suggested that COVID-19 is associated with an increased risk of developing various ADs and the risk could be attenuated by COVID-19 vaccination. Future studies investigating pathology and mechanisms would be valuable to interpreting our findings. Supported by RGC Collaborative Research Fund (C7154-20GF).

Drug-induced immune-mediated thrombocytopenia due to bevacizumab-FOLFOX therapy: a case report

Drug-induced immune thrombocytopenia (DITP) is a very rare disease, with an estimated annual incidence of 10 cases per million. Oxaliplatin and irinotecan are widely used as chemotherapy for high-risk stage II and III colorectal cancer, and DITP has been reported to occur in patients using those agents. To treat unresectable metastatic colorectal cancer, bevacizumab is used in combination with oxaliplatin or irinotecan, and there have been a few reports of DITP cases in patients receiving that regimen. In this report, we describe a 68-year-old male patient with metastatic colon cancer (KRAS mutant type) to the liver and lung who developed acute immune-mediated thrombocytopenia due to bevacizumab-FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) therapy. During treatment, he showed purpura in his lower extremities on 21st cycle day 2. Lab work revealed a platelet count of less than 2,000/mL, reflecting a decrease from 135,000/mL at the start of the cycle 1 day prior. He did not have any other types of cytopenia or significant changes in laboratory findings. We diagnosed DITP due to bevacizumab-FOLFOX, and the patient did not show isolated thrombocytopenia after switching to Ziv-aflibercept-FOLFIRI (5-fluorouracil, leucovorin, and irinotecan).

Babesia gibsoni Infection in a Cat with Immune-Mediated Haemolytic Anaemia and Thrombocytopenia

Tick-borne haemoparasite Babesia gibsoni has been detected rarely in cats, in surveys of apparently healthy animals. In stored blood from a 6-year-old male-neutered domestic shorthair cat in Hong Kong, B. gibsoni DNA was detected retrospectively using PCR for Babesia spp. 18S rRNA and mitochondrial cytochrome B genes, followed by sequencing and basic local alignment search tool (BLAST) analysis. The cat presented with severe haemolytic anaemia and thrombocytopenia. The cat responded to supportive care and glucocorticoids and was clinically normal despite persistent subclinical thrombocytopenia until six months after presentation, when it succumbed to a fatal haemorrhagic episode. Necropsy revealed severe intestinal and pulmonary haemorrhage and hypocellular bone marrow with megakaryocytosis but no other causes of immune-mediated thrombocytopenia (IMTP) or immune-mediated haemolytic anaemia (IMHA). Blood stored on days 158 and 180 tested PCR negative for Babesia spp. This report demonstrates that geographic range of B. gibsoni detection in cats includes Hong Kong. The exclusion of other causes suggests that B. gibsoni might have potentially played a role in triggering immune-mediated disease in this case.

Immune-Mediated Thrombocytopenia in adults: Treatment Updates

Immune Thrombocytopenia (ITP) is an acquired low platelet count resulting from immune-mediated platelet destruction and/ or impaired platelet production. Primary ITP is idiopathic and secondary ITP is associated with another conditions. The incidence is 1 to 6 per 100,000 adults. ITPmay present without symptom or present with bleeding. Bleeding manifestations are minor (skin/mucous membrane), critical (e.g. intracranial, intraocular, retroperitoneal, intramuscular bleeding etc) and severe (fall in hemoglobin of 2 g/dL or requires transfusion of e”2 units of red cells).ITP is diagnosed on the basis of isolated thrombocytopenia without anemia or leukopenia. There are no reliable laboratory tests to confirm the diagnosis. The aim of treatment of ITP is to provide a safe platelet count to prevent bleeding, rather than to normalize the platelet count. Treatment options of ITP are the Firstline therapies, second-line therapies and therapies. First-line therapy are for patients with severe bleeding and platelet count &lt;30x10^9/L, which includes platelet transfusion, glucocorticoids (e.g. methylprednisolone, 1 g IV, daily for 3 doses; or dexamethasone, 40 mg orally or IV, daily for four days), IVIG and IV globulin. Second-line therapy is indicated for patients with thrombocytopenia associated with significant bleeding or for severe, persistent or recurrent thrombocytopenia (e.g., platelet count &lt;20x10^9/L) following glucocorticoid-based treatments. Secondline therapies include splenectomy, rituximab, thrombopoietin receptor agonist or immunosuppressive therapy. Other therapies include danazol, vincristine, procarbazine, etoposide etc, or combination therapy. Indications of treatment are (1).Severe bleeding and platelet count &lt;30x10^9/L. (2). Newly diagnosed ITP and any clinically important bleeding (3) Newly diagnosed ITP and platelet count &lt;20x10^9/L, even in absence of bleeding (4) Patients with platelet counts &gt;30x10^9/L having risk of bleeding, other hemostatic defects or require surgery.Spontaneous remission occurs in up to 10% of adults with ITP. Bangladesh J Medicine 2023; Vol. 34, No. 2(1) Supplement: 189-190

Causes of thrombocytopenia in dogs in the United Kingdom: A retrospective study of 762 cases.

Thrombocytopenia is a common laboratory abnormality in dogs, and numerous diseases have been associated with its development. Estimates for the sensitivity and specificity of the degree of reduction of platelet concentration for the diagnosis of primary immune-mediated thrombocytopenia (pITP) have not been reported. To report the prevalence of different causes of thrombocytopenia in dogs in the United Kingdom and to investigate the utility of platelet concentration to differentiate causes of thrombocytopenia. Medical records of 762 dogs with thrombocytopenia presented to seven referral hospitals from January 2017 to December 2018 were retrospectively reviewed. Cases were assigned into the following categories: pITP, infectious diseases, neoplasia, inflammatory/other immune-mediated disorders and miscellaneous causes. The prevalence of the different categories was estimated, and platelet concentrations were compared. Receiver-operating characteristic (ROC) curves were used to investigate the utility of platelet concentration to differentiate between causes of thrombocytopenia. The most common disease category associated with thrombocytopenia was neoplasia (27.3%), followed by miscellaneous causes (26.9%), pITP (18.8%), inflammatory/immune-mediated disorders (14.4%) and infectious diseases (12.6%). Dogs with pITP had significantly lower platelet concentrations (median 8×109 /L, range: 0-70×109 /L) than dogs in the other four categories. Platelet concentration was useful for distinguishing pITP from other causes of thrombocytopenia (area under ROC curve=0.89, 95% confidence interval 0.87, 0.92), with a platelet concentration ≤12×109 /L being 60% sensitive and 90% specific. Severe thrombocytopenia was highly specific for a diagnosis of pITP, which was more prevalent in this UK population of thrombocytopenic dogs compared with previous epidemiological studies. Conversely, the proportion of dogs with infectious diseases was lower than in previous reports from other locations.

Cerebral venous sinus thrombosis associated with SRA-negative heparin-induced thrombocytopenia: case report

BackgroundThere are very few documented reports in literature of cerebral venous sinus thrombosis (CVST) caused by immune-mediated heparin-induced thrombocytopenia (HIT). Further, there are very few reports of false negative serotonin release assays (SRAs) when testing for immune-mediated HIT.Case presentationWe present a case of a 60- year-old male with recent unfractionated heparin administration for venous thromboembolism prophylaxis, an elevated 4T score of 5 and acute CVST in which immune-mediated HIT was suspected. The enzyme-linked immunosorbent assay (ELISA) screening assay was positive for PF4 antibodies and subsequent reflexive SRA testing was negative. However, given the clinical picture, a false-negative SRA was suspected (and eventually confirmed), prompting use of the alternative PF4-dependent p-selectin expression assay (PEA) which was confirmed to be positive. The patient was successfully managed with a bivalirudin infusion and eventually transitioned to apixaban.ConclusionIt is uncommon for immune-mediated HIT with thrombosis to manifest as CVST. Similarly, false-negative SRA is uncommon in immune-mediated HIT. Take-away lessons from our case report include considering HIT in CVST patients with an elevated 4T score and considering the entire clinical picture and degree of suspicion for HIT when interpreting negative HIT testing results. The PEA, in conjunction with the 4Ts score, may be considered as an alternate diagnostic assay for HIT.

Human intravenous immunoglobulin use for hematological immune-mediated disease in dogs.

To report on survival rates and risk factors in dogs with immune-mediated hemolytic anemia (IMHA) and immune-mediated thrombocytopenia (ITP) treated with human IV immunoglobulin (hIVIG; Privigen). We hypothesized that hIVIG could be used as a salvage treatment to improve survival and reduce the requirement for ongoing blood transfusion therapy in IMHA and ITP patients. 52 client-owned dogs with IMHA or ITP were included, comprising 31 females (28 spayed and 3 entire) and 21 males (19 castrated and 2 entire). Miniature Schnauzers were the most common breed (5), with a further 24 different breeds identified. A retrospective cohort study was conducted between January 2006 and January 2022 that assessed the survival rates, risk factors, and need for ongoing transfusion in dogs with IMHA and ITP treated with hIVIG compared with those not receiving hIVIG. Of 36 dogs that did not receive hIVIG, 29 (80%) survived and 7 (24%) died, and of 16 dogs administered hIVIG, 11 (69%) survived and 5 (31%) died (P = .56). No effect of PCV at admission or age on the risk of death was detected (OR, 1.00; 95% CI, 0.94 to 1.08; P = .89; and OR, 1.10; 95% CI, 0.85 to 1.47; P = .47, respectively). This was the largest study to date of dogs with hematological immune-mediated disease treated with hIVIG. There was no difference in survival rates for dogs that received hIVIG versus those treated with standard immunosuppression. The benefit of hIVIG as a salvage treatment appears limited.