The use of 1E12, a monoclonal anti-platelet factor 4 antibody, to improve the diagnosis of vaccine-induced immune thrombotic thrombocytopenia.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a complication of adenoviral-based vaccine against SARS-CoV-2 due to prothrombotic immunoglobulin (Ig) G antibodies to platelet factor 4 (PF4) and may be difficult to distinguish from heparin-induced thrombocytopenia (HIT) in patients treated with heparin. OBJECTIVES: We assessed the usefulness of competitive anti-PF4 enzyme immunoassays (EIAs) in this context. METHODS: The ability of F(ab')2 fragments of 1E12, 1C12, and 2E1, 3 monoclonal anti-PF4 antibodies, to inhibit the binding of human VITT or HIT antibodies to PF4 was evaluated using EIAs. Alanine-scanning mutagenesis was performed to define the amino acids involved in the interactions between the monoclonal antibodies and PF4. RESULTS: A strong inhibition of VITT IgG binding to PF4 was measured with 1E12 (median inhibition, 93%; n = 8), whereas it had no effect on the binding of HIT antibodies (median, 6%; n = 8). In contrast, 1C12 and 2E1 inhibited VITT (median, 74% and 76%, respectively) and HIT antibodies (median, 68% and 53%, respectively) binding to PF4. When a competitive anti-PF4 EIA was performed with 1E12 for 19 additional VITT samples, it strongly inhibited IgG binding to PF4, except for 1 patient, who had actually developed HIT according to the clinical history. Epitope mapping showed that 1E12 interacts with 5 key amino acids on PF4, of which 4 are also required for the binding of human VITT antibodies, thus explaining the competitive inhibition. CONCLUSION: A simple competitive anti-PF4 EIA with 1E12 could help confirm VITT diagnosis and distinguish it from HIT in patients when both diagnoses are possible.

Hydroxychloroquine-Induced Nonthrombocytopenic Purpura: A Case Series.

Hydroxychloroquine (HCQ) is a disease-modifying anti-rheumatic medication for the treatment of various autoimmune conditions. A rare side effect of HCQ is thrombotic thrombocytopenic purpura (TTP). We present two cases of patients who developed purpura that did not meet TTP criteria following treatment with HCQ. While the etiology of HCQ-associated TTP is poorly understood, we propose a spectrum of manifestations related to HCQ, ranging from benign purpura to TTP. As multiple factors contribute to the disease, we believe that HCQ may act as a "second hit" in patients with genetic susceptibility, which also influences the variability in the severity of disease manifestations. J Drugs Dermatol. 2024;23(5):e124.     doi:10.36849/JDD.7781e.

Structural Characterization of a Pathogenic Antibody Underlying Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT).

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but dangerous side effect of adenoviral-vectored COVID-19 vaccines. VITT had been linked to production of autoantibodies recognizing platelet factor 4 (PF4). Here, we characterize anti-PF4 antibodies obtained from a VITT patient's blood. Intact mass measurements indicate that a significant fraction of these antibodies represent a limited number of clones. MS analysis of large antibody fragments (the light chain and the Fc/2 and Fd fragments of the heavy chain) confirms the monoclonal nature of this component of the anti-PF4 antibodies repertoire and reveals the presence of a mature complex biantennary N-glycan within the Fd segment. Peptide mapping using two complementary proteases and LC-MS/MS was used to determine the amino acid sequence of the entire light chain and over 98% of the heavy chain (excluding a short N-terminal segment). The sequence analysis allows the monoclonal antibody to be assigned to the IgG2 subclass and verifies that the light chain belongs to the λ-type. Incorporation of enzymatic de-N-glycosylation into the peptide mapping routine allows the N-glycan in the Fab region of the antibody to be localized to the framework 3 region of the VH domain. This novel N-glycosylation site is the result of a single mutation within the germline sequence. Peptide mapping also provides information on lower-abundance (polyclonal) components of the anti-PF4 antibody ensemble, revealing the presence of all four subclasses (IgG1-IgG4) and both types of the light chain (λ and κ). This case study demonstrates the power of combining the intact, middle-down, and bottom-up MS approaches for meaningful characterization of ultralow quantities of pathogenic antibodies extracted directly from patients' blood.

[Acquired thrombotic thrombocytopenic purpura during durvalumab monotherapy for non-small cell lung cancer].

Immune checkpoint inhibitor (ICI)-induced thrombocytopenias are rare immune-related adverse events (irAE), but ICI-related thrombotic thrombocytopenic purpura (TTP) is extremely rare. A 79-year-old woman with non-small cell lung cancer received maintenance therapy with the anti-human PD-L1 monoclonal antibody durvalumab. Four weeks after the last infusion, she developed overt TTP. Remission was achieved by plasma exchange and prednisolone, and the patient has now been recurrence-free for over 12 months. To our knowledge, this is the first report of TTP occurring as an irAE of durvalumab.

Alemtuzumab-induced immune-mediated thrombotic thrombocytopenic purpura: A newly described drug-related autoimmune disease.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening disease that may result from drug exposure. We report a case of iTTP occurring in a 39-year-old patient, 45 months following introduction of the anti-CD52 lymphoid cell depleting monoclonal antibody alemtuzumab, to treat a relapsing-remitting multiple sclerosis. Treatment consisted in plasma exchange, corticosteroids and caplacizumab, allowing clinical remission 3 months after the diagnosis, attested by the absence of thrombocytopenia and recovery of ADAMTS-13 activity. As other autoimmune disorders, iTTP may occur following alemtuzumab. This diagnosis should be suspected in patients with features of thrombotic microangiopathy following this treatment.

Clopidogrel-induced thrombotic thrombocytopenic purpura: a case report.

Thrombotic thrombocytopenic purpura (TTP) is a rare variant of thrombotic microangiopathy. We report a case of TTP in a Nigerian chronic kidney disease (CKD) patient who was previously on clopidogrel. The features of TTP resolved soon after clopidogrel was withdrawn. Clopidogrel is a cardio-protective anti-platelet drug used in CKD patients at risk of dyspepsia. However, its potential to cause TTP should be recognized and considered in acute kidney injury (AKI) patients previously on clopidogrel.

Durable remission of thrombotic thrombocytopenic purpura in the setting of pembrolizumab therapy.

BACKGROUND: There is a small but growing number of thrombotic thrombocytopenic purpura (TTP) cases attributed to immune checkpoint inhibitor therapy, with nivolumab and ipilimumab therapy being the most frequently described in the literature. STUDY DESIGN AND METHODS: This report evaluates the course of a patient with a history of metastatic adenocarcinoma of the lung who developed TTP following treatment with the PD-1 inhibitor Pembrolizumab. The patient was treated with six sessions of therapeutic plasma exchange and appeared to be in remission. Exacerbation occurred 4 days later, and seven more sessions of plasma exchange were performed along with four total doses of Rituximab, and a steroid taper with monitoring of platelet counts and ADAMTS13 activity. RESULTS: His platelet count recovered to a peak of 318,000 UL with an ADAMTS13 activity of 77% at the time of discharge. The patient has been following up regularly for outpatient testing with no TTP relapse as of the completion of this report. DISCUSSION: This is one of a few cases of Pembrolizumab-associated TTP reported in the literature with successful complete remission following treatment. Plasma exchange in this setting may be an especially beneficial therapeutic intervention because of the removal of both the anti-ADAMTS13 antibody as well as the immune system upregulating anti-PDL1 monoclonal antibody with replacement of ADAMTS13 from donor plasma. Longer duration of plasma exchange and monitoring for normalization of ADAMTS13 levels in addition to platelet count before cessation of treatment may improve durable remission rates in this entity.

A 'needle in a haystack': Drug-induced thrombotic thrombocytopenic purpura-Association or causality?

The risk of a drug associated with thrombotic thrombocytopenic purpura (TTP) demonstrating causality is rare, but it is important to keep an open mind of possible associations. Use of criteria to ascertain causality of drugs that may be related to thrombotic microangiopathies and exclude TTP, may be a useful resource. Commentary on: Schofield et al. Drug-induced thrombotic thrombocytopenic purpura: A systematic review and review of European and North American pharmacovigilance data. Br J Haematol 2023;200:766-773.

Drug-induced thrombotic thrombocytopenic purpura: A systematic review and review of European and North American pharmacovigilance data.

Many medications have been reported to be associated with thrombotic thrombocytopenic purpura (TTP) through pharmacovigilance data and published case reports. Whilst there are existing data available regarding drug-induced thrombotic microangiopathy, there is no available synthesis of evidence to assess drug-induced TTP (DI-TTP). Despite this lack of evidence, patients with TTP are often advised against using many medications due to the theoretical risk of DI-TTP. This systematic review evaluated the evidence for an association of medications reported as potential triggers for TTP. Of 5098 records available 261 articles were assessed further for eligibility. Fifty-seven reports, totalling 90 patients, were included in the final analysis. There were no cases where the level of association was rated as definite or probable, demonstrating a lack of evidence of any drug causing DI-TTP. This paucity of evidence was also demonstrated in the pharmacovigilance data, where 613 drugs were reported as potential causes of TTP without assessment of the strength of association. This systematic review demonstrates the need for standardised reporting of potential drugs causing TTP. Many reports omit basic information and, therefore, hinder the chance of finding a causative link if one exists.

Semi-selective plasma filtration applied to the treatment of acquired thrombotic thrombocytopenic purpura following bnt162b2 administration.

Following the widespread use of anti SARS-CoV-2 vaccines, there have been reports of thrombocytopenia developing after the administration of different types of vaccine. We report a case of a 63-year-old male who developed neurological symptoms after receiving the second dose of the bnt162b2 vaccine. Blood tests performed upon admission to the Emergency Department revealed severe thrombocytopenia and microangiopathic hemolytic anemia. ADAMTS13 activity was undetectable and antibody titer was high. Due to the rapid neurological deterioration, steroid therapy with prednisone was started at an initial dose of 1 mg/kg/day. Rituximab therapy was started to prevent the formation of new antibodies. Given the slow response to this therapy, we added Caplacizumab, (a monoclonal antibody anti-Von Willebrand factor) in order to inhibit platelet hyperaggregation, combined with standard plasma exchange. The patient experienced repeated episodes of intolerance to fresh frozen plasma (FFP). Switching from plasma exchange to plasma filtration, remission was attained in this unusual case of vaccine-related thrombocytopenia with microangiopathic hemolytic anemia.

Mild forms of thrombotic microangiopathy in patients with advanced pancreatic cancer receiving gemcitabine and nab-paclitaxel.

INTRODUCTION: Thrombotic microangiopathy (TMA) is an uncommon complication that may occur in cancer patients usually as an expression of cancer-associated coagulopathy or due to drug-related toxicity. The clinical spectrum of TMA may vary from an incidental laboratory finding in cancer outpatients to potentially severe life-threatening clinical forms with organ involvement requiring prompt recognition and multidisciplinary evaluation. CASE REPORTS: We present the clinical characteristics and outcomes of four patients with advanced pancreatic cancer with acute non-immune intravascular haemolysis compatible with microangiopathic acute haemolytic anaemia associated with mild thrombocytopenia during long-term gemcitabine and nab-paclitaxel treatment. MANAGEMENT AND OUTCOMES: Abnormal blood parameters (all four cases) and renal involvement (one case) were reversed with a conservative approach and chemotherapy discontinuation. One patient required a short hospitalization while the other three were managed as outpatients. The rapid reversibility of the blood abnormalities supported gemcitabine dose-related toxicity as the most likely aetiologic mechanism and demonstrates the current challenges in daily long-term cancer survivor care. DISCUSSION: Clinicians must take into account TMA in the differential diagnosis of acute anaemia with or without thrombocytopenia and organ damage, since adequate recognition and early treatment discontinuation allow effective outpatient management and favourable patient outcomes.

Thrombotic thrombocytopenic purpura developed after pegylated interferon treatment for hepatitis B infection.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia. It is related to severe deficiency in ADAMTS13, which is usually acquired via ADAMTS13 autoantibodies or inherited via mutations of the ADAMTS13 gene. The etiology of acquired TTP including HIV infection, pregnancy, autoimmune disease, organ transplantation, drugs, malignancy and so on. Here, we firstly reported a patient diagnosed as acquired TTP after pegylated interferon therapy for hepatitis B and COVID-19 vaccination. CASE PRESENTATION: A 36-year-old male attended to our unit with a five-day history of intermittent hematuria and progressive fatigue on January 5th, 2022. He had a 13 years history of hepatitis B infection and undergone pegylated interferon treatment (which was paused for two months because of COVID-19 vaccination) for nearly 3 years. Laboratory evaluation revealed a haemoglobin level of 61 g/L, platelet count of 11 × 109/L, lactate dehydrogenase 2133 U/L. The direct and indirect Coombs test were both negative. On a peripheral blood smear, there were about 18.8% schistocytes. Meanwhile, the results of ADAMTS 13 activity and antibody were < 5% and 181.34 ng/ml (131.25-646.5), respectively CONCLUSION: This case firstly reported the rare complication of TTP after pegylated interferon treatment for hepatitis B and COVID-19 vaccine injection. This unique sign warrants more attention as an early cue of diagnosis of TTP and be aware of the rarity adverse effect of interferon therapy and COVID-19 vaccination.

An 80-Year-Old Man with Ischemic Heart Disease Who Developed Thrombotic Thrombocytopenic Purpura Following Treatment with Ticagrelor.

BACKGROUND Thrombotic thrombocytopenic purpura (TTP) is associated with widespread microvascular thrombosis, low platelet count, and hemolysis. Ticagrelor is a relatively new agent which functions as a reversible inhibitor of the P2Y12 receptor working to prevent platelet aggregation and is used with or without aspirin in patients with acute coronary syndrome to reduce the risk of myocardial infarction and stroke. We describe the case of an 80-year-old man with ischemic heart disease who developed this rare and potentially fatal adverse reaction known as TTP following treatment with ticagrelor. CASE REPORT We report the case of an 80-year-old man who presented with an acute change in mental status 4 months after initiating ticagrelor following percutaneous coronary intervention. Laboratory testing on presentation revealed evidence of microangiopathic hemolytic anemia, thrombocytopenia, and elevated creatinine levels, suggestive of acute renal failure. The combination of his clinical symptoms and laboratory findings were concerning for TTP, likely secondary to ticagrelor use. The patient was treated with therapeutic plasma exchange, systemic steroids, and hemodialysis, which led to resolution of the hemolysis and recovery of renal function. CONCLUSIONS Although the association between ticagrelor and TTP is rare, early recognition of this life-threatening complication is essential to decrease morbidity and mortality associated with TTP. Since ticagrelor is now more commonly used, it is important that clinicians be aware of this complication.

Relapse of immune thrombotic thrombocytopenic purpura (iTTP) possibly triggered by COVID-19 vaccination and/or concurrent COVID-19 infection.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that may be triggered by inflammation, including infection or vaccination. Since the start of the COVID-19 pandemic, several case reports were published on de novo or relapsed immune TTP (iTTP) in COVID-19-infected patients. Case reports of iTTP episodes following vaccination against COVID-19 are also emerging. We report a case of relapsed iTTP in a patient who received Moderna mRNA-1273 SARS-CoV-2 vaccine and developed concurrent severe COVID-19 infection. The patient's iTTP was successfully managed with caplacizumab, therapeutic plasma exchange and high-dose steroids. We summarise published cases of iTTP associated with COVID-19 infection or vaccination.

Acquired thrombotic thrombocytopenic purpura associated with immune checkpoint inhibitors: A real-world study of the FDA adverse event reporting system.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are used for a variety of cancers and are associated with a risk of developing immune-related adverse events, most commonly colitis, dermatitis, hepatitis, and thyroiditis. Rare autoimmune hematologic toxicities have been reported but are less well-described in the literature. Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening autoimmune condition that has been reported with ICIs but has been limited to case reports. METHODS: We performed a retrospective observational analysis of the United States Food and Drug Administration Adverse Event Reporting System (FAERS) data. We searched for cases of TTP reported with exposure to ICIs from initial FDA approval for each agent to December 31, 2021. Disproportionality signal analysis was done by calculating the reporting odds ratio (ROR). RESULTS: There were 35 reports of TTP with ICIs in the FAERS database, including atezolizumab (n = 7), durvalumab (n = 2), nivolumab (n = 18), and pembrolizumab (n = 8). The ROR was significant for atezolizumab (ROR 6.22, 95% CI 2.96-13.09), nivolumab (ROR 3.16, 95% CI 1.99-5.03), and pembrolizumab (ROR 2.56, 95% CI 1.28-5.12). CONCLUSIONS: There is a significant reporting signal of TTP with several ICI agents. Clinicians should be aware of and monitor for signs of this potentially serious adverse event.

Case Report: Rabies Vaccine-Induced Thrombotic Thrombocytopenic Purpura in a Patient With Systemic Lupus Erythematosus.

For patients with autoimmune diseases, vaccination is controversial. The use of vaccination in patients with autoimmune diseases is controversial. There are many reports of secondary thrombotic thrombocytopenic purpura cases after various vaccinations. Thrombotic thrombocytopenic purpura is a rare thrombotic microangiopathy characterized by microvascular pathological hemolytic anemia, severe thrombocytopenia, and ischemic organ damage with a very high fatality rate. We report a case of thrombotic thrombocytopenic purpura in a patient with systemic lupus erythematosus after rabies vaccination. She developed gastrointestinal bleeding nearly a month after the vaccination. Laboratory tests confirmed a severe deficiency of ADAMTS13 and the presence of ADAMTS13 autoantibodies. Through early identification of thrombotic thrombocytopenic purpura, immunosuppressive therapy, and plasma exchange treatment, the patient was saved from danger. This case suggests that attenuated vaccines may also have unexpected adverse effects in patients with long-term use of immunosuppressive drugs and autoimmune diseases. To our knowledge, this is the first case report of thrombotic thrombocytopenic purpura in a patient with systemic lupus erythematosus secondary to rabies vaccination.