Diabetic Ketoacidosis Complicated by Thrombotic Thrombocytopenic Purpura: A Rare Association.

Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially life-threatening blood disorder caused by a deficiency or dysfunction of ADAMTS13 and can occur secondary to various conditions, including autoimmune diseases, infections, medications, pregnancy, and malignancies. Diabetic ketoacidosis (DKA) inducing TTP is uncommon and not widely reported in the literature. Herein, we report a case of TTP induced by DKA in an adult patient. His clinical picture, serological, and biochemical results confirmed the diagnosis of TTP induced by DKA, and his clinical course did not improve despite normalization of glucose level, plasmapheresis, and aggressive management. Our case report emphasizes the importance of considering TTP as a potential complication of DKA.

Automated and Rapid ADAMTS13 Testing Using Chemiluminescence: Utility for Identification or Exclusion of TTP and Beyond.

Thrombotic thrombocytopenic purpura (TTP) is a prothrombotic condition caused by a significant deficiency of the enzyme, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). In the absence of adequate levels of ADAMTS13 (i.e., in TTP), plasma VWF accumulates, in particular as "ultra-large" VWF multimers, and this leads to pathological platelet aggregation and thrombosis. In addition to TTP, ADAMTS13 may be mildly to moderately reduced in a range of other conditions, including secondary thrombotic microangiopathies (TMA) such as those caused by infections (e.g., hemolytic uremic syndrome (HUS)), liver disease, disseminated intravascular coagulation (DIC), and sepsis, during acute/chronic inflammatory conditions, and sometimes also in COVID-19 (coronavirus disease 2019)). ADAMTS13 can be detected by a variety of techniques, including ELISA (enzyme-linked immunosorbent assay), FRET (fluorescence resonance energy transfer) and by chemiluminescence immunoassay (CLIA). The current report describes a protocol for assessment of ADAMTS13 by CLIA. This protocol reflects a rapid test able to be performed within 35 min on the AcuStar instrument (Werfen/Instrumentation Laboratory), although certain regional approvals may also permit this testing to be performed on a BioFlash instrument from the same manufacturer.

Renal Thrombotic Microangiopathy: A Review.

Thrombotic microangiopathy (TMA), a pathological lesion observed in a wide spectrum of diseases, is triggered by endothelial injury and/or dysfunction. Although TMA lesions are often accompanied by clinical features of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic end-organ injury, renal-limited forms of TMA are not infrequently encountered in clinical practice. The presence of renal-limited manifestations can be diagnostically challenging, often delaying the initiation of targeted therapy. Prompt investigation and empirical treatment of TMA is warranted to reduce associated morbidity and mortality. Major advances have been made with respect to the pathophysiology of primary TMA entities, with the subsequent development of novel diagnostic tools and lifesaving therapies for diseases like thrombotic thrombocytopenic purpura and complement-mediated TMA. This article will review the clinical presentation and pathologic hallmarks of TMA involving the kidney, and the disease-specific mechanisms that contribute to the endothelial injury that characterizes TMA lesions. Diagnostic approach and both empirical and disease-specific treatment strategies will be discussed, along with the potential role for emerging targeted disease-specific therapies.

Epidermolysis Bullosa Acquisita in a patient with End Stage Renal Disease: Case study.

The clinical presentation of COVID-19 varies from being asymptomatic to developing acute respiratory distress syndrome and multi-organ dysfunction. The diffuse microvascular thrombi in multiple organs seen in the autopsy of COVID-19 patients are similar to that of thrombotic microangiopathy (TMA). TMA is characterised by thrombus formation in the microvasculature with laboratory findings of microangiopathic haemolytic anaemia (MAHA) and thrombocytopenia. A 49-year-old male presented to the Aga Khan University Hospital, Karachi. with fever, diarrhoea, altered level of consciousness, and a positive nasopharyngeal swab for SARS-CoV-2. He developed severe thrombocytopenia, MAHA with 5.8% schistocytes, and worsening renal function on the sixth day of admission. Diagnosis of thrombotic thrombocytopenic purpura (TTP) was established based on PLASMIC score, and he was successfully treated with intravenous (IV) Methylprednisolone, therapeutic plasma exchange and IV Rituximab. The case emphasises the need to keep TTP in the differential diagnosis when a patient with COVID-19 develops severe thrombocytopenia, acute renal failure, or impaired level of consciousness, since prompt diagnosis and treatment is necessary to gain favourable outcome.

Thrombotic Thrombocytopenic Purpura (TTP) secondary to Covid-19 infection in a patient with Systemic Lupus Erythematosus (SLE)

Background: Covid-19 infection has caused a global pandemic in the recent years and although initially it was considered mainly a respiratory ailment it has proven over time to cause a constellation of complications across various systems such as hematological, immune, cardiovascular, gastrointestinal, and neurological. Method(s): We report a case of a lupus patient with Covid-19 infection who presented initially with fever and gum bleeding with a negative dengue serology and negative HIV serology. Result(s): A 45-year- old lady with a 30-year history of SLE was admitted to our hospital with Covid 19 infection. She had relatively stable disease over the past few years but was admitted to the hospital with complaints of fever, gum bleeding and shortness of breath with no chest x-ray changes. Her oxygen saturations were 95% under room air and her vital signs were stable. Laboratory examinations revealed raised white cell count (11.63) with neutrophilia and elevated C-reactive protein (2.84mg/dl). Her platelet count was low at 113 when compared to her baseline of 549. An urgent peripheral blood film showed an incidental finding of Stomato-ovalocytosis with mild anaemia however there was no features of haemolysis. She was initially treated as acquired Immune thrombocytopenia provoked by Covid-19 infection and was started on IV hydrocortisone. She had a lack of response as evident of a further decline in her platelet counts and the following day, she developed rapid decline in her renal function wherein her creatinine increased from 83 to 207. An urgent ultrasound doppler of the kidneys to rule out acute renal vein thrombosis was organised however it showed normal patent renal vessels. Peripheral blood films were repeated which showed minimal schistocytes and the diagnosis was clinched with the Adamst13 activity levels being less than 0.2%. She was started on 20g IVIG per day with plasma exchange however succumbed to the illness. Conclusion(s): The diagnosis of TTP classically involves the recognition of the pentad of fever, microangiopathic hemolytic anemia, thrombocytopenia, acute renal failure, and neurological abnormalities however 60% of patients do not fulfil the pentad. It is essential to recognize that Covid-19 is an acquired cause of TTP, and a high index of suspicion must be maintained for early treatment institution.

COVID-19 Adenoviral Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT), COVID-19-Related Thrombosis, and the Thrombotic Thrombocytopenic Syndromes.

Adenoviral-based vaccines such as ChadoX1 CoV-19 (AstraZeneca) and Ad26.COV2.S (J&J) were developed to prevent infection and reduce hospitalization or death in Coronavirus Disease 2019 (COVID-19) patients. Although these vaccines passed safety and efficacy trials with excellent neutralizing capabilities against SARS-CoV-2, very rare reports of acute thrombotic thrombocytopenic events following administration emerged in certain populations, which triggered a series of clinical investigations that gave rise to a novel phenomenon called vaccine-induced immune thrombotic thrombocytopenia (VITT). Several converging pathways exist between VITT and other forms of thrombotic thrombocytopenic syndromes, specifically that of heparin-induced thrombocytopenia, which involves the formation of anti-PF4 antibodies and the activation of platelets leading to thrombocytopenia and thrombin-mediated clotting. Interestingly, certain differences in the presentation also exist in VITT, and guidelines have been published in recent months to assist clinicians in recognizing VITT to achieve desired outcomes. In this paper, we first discuss the clotting phenomenon in COVID-19 and delineate it from VITT, followed by a review of current knowledge on the clinical manifestations of VITT in lieu of other thrombotic thrombocytopenic syndromes. Likewise, emerging evidence on the role of adenoviral vectors and vaccine constituents is also discussed briefly.

Immune-mediated thrombotic thrombocytopenic purpura in a Jehovah's Witness - Effectiveness of incorporating extracorporeal immunoadsorption to caplacizumab, steroids and rituximab.

We report the case of a Jehovah's Witness adolescent patient with immune-mediated thrombotic thrombocytopenic purpura after SARS-Cov2 infection successfully treated without therapeutic plasma exchange (TPE) using caplacizumab, corticosteroids, rituximab, and extracorporeal immunoadsorption (EIA). Further patients for whom TPE is not an option might benefit from this approach.

COVID-19 Vaccines and Autoimmune Hematologic Disorders.

Worldwide vaccination against SARS-CoV-2 has allowed the detection of hematologic autoimmune complications. Adverse events (AEs) of this nature had been previously observed in association with other vaccines. The underlying mechanisms are not totally understood, although mimicry between viral and self-antigens plays a relevant role. It is important to remark that, although the incidence of these AEs is extremely low, their evolution may lead to life-threatening scenarios if treatment is not readily initiated. Hematologic autoimmune AEs have been associated with both mRNA and adenoviral vector-based SARS-CoV-2 vaccines. The main reported entities are secondary immune thrombocytopenia, immune thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia, Evans syndrome, and a newly described disorder, so-called vaccine-induced immune thrombotic thrombocytopenia (VITT). The hallmark of VITT is the presence of anti-platelet factor 4 autoantibodies able to trigger platelet activation. Patients with VITT present with thrombocytopenia and may develop thrombosis in unusual locations such as cerebral beds. The management of hematologic autoimmune AEs does not differ significantly from that of these disorders in a non-vaccine context, thus addressing autoantibody production and bleeding/thromboembolic risk. This means that clinicians must be aware of their distinctive signs in order to diagnose them and initiate treatment as soon as possible.

COVID-19-Associated Thrombotic Thrombocytopenic Purpura: A Case Report and Systematic Review.

INTRODUCTION: The proliferation of literature regarding the COVID-19 pandemic has served to highlight a wide spectrum of disease manifestations and complications, such as thrombotic microangiopathies. Our review with a brief case presentation highlights the increasing recognition of TTP in COVID-19 and describes its salient characteristics. METHODS: We screened the available literature in PubMed, EMBASE, and Cochrane databases from inception until April 2022 of articles mentioning COVID-19-associated TTP in English language. RESULTS: From 404 records, we included 8 articles mentioning data of 11 patients in our review. TTP was predominantly reported in females (72%) with a mean age of 48.2 years (SD 15.1). Dyspnea was the most common symptom in one third of patients (36.6%). Neurological symptoms were reported in 27.3% of cases. The time to diagnosis of TTP was 10 days (SD 5.8) from onset of COVID-19. All 11 cases underwent plasma exchange (PLEX), with a mean of 12 sessions per patient, whereas 6 cases received Rituximab (54.5%), and 3 received Caplacizumab (27.3%). One patient died from the illness. CONCLUSION: This review of available literature highlights the atypical and refractory nature of COVID-19-associated TTP. It required longer sessions of PLEX, with half of the patients receiving at least one immunosuppressant.

The use of obinutuzumab and ofatumumab in the treatment of immune thrombotic thrombocytopenic purpura.

Rituximab, an anti-CD20 monoclonal antibody, can be used to treat immune thrombotic thrombocytopenic purpura (iTTP) during acute presentation or disease relapse. Undesirable side-effects include severe hypersensitivity reactions, particularly anaphylaxis and rituximab-induced serum sickness, with a minority not maintaining a response to treatment. Alternative humanised anti-CD20 treatments, obinutuzumab and ofatumumab, have been used. A review of the UK TTP Registry showed 15 patients received these drugs over 26 treatment episodes (eight obinutuzumab and 18 ofatumumab). Indications for alternative anti-CD20 treatment were severe infusion-related reactions, acute rituximab-induced serum sickness and a short duration of disease remission. All patients achieved disease remission (ADAMTS13 [A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13] activity ≥30 iu/dl) after a median 15 days and 92% of episodes achieved complete remission (≥60 iu/dl). Seven patients required further treatment for disease relapse with a median relapse-free survival of 17.4 months. All patients continued to respond to re-treatment with the preceding drug when relapse occurred. There were four adverse events in 26 treatment episodes (15%) - two infections and two infusion reactions. These results suggest that obinutuzumab and ofatumumab may be considered as an alternative option to rituximab in the treatment of iTTP with a comparable safety profile, absence of significant hypersensitivity reactions and sustained normalisation of ADAMTS13.

Acquired thrombotic thrombocytopenic purpura after AstraZeneca vaccine: A case report.

Background: Rare cases of acquired thrombotic thrombocytopenic purpura (aTTP) have been reported since the administration of the COVID-19 vaccination. Based on our information, the present study provides the first case report of aTTP developed after the COVID-19 vaccination in Iran. Case presentation: A 22-year-old Iranian woman presented with symptoms of ataxia, dysphasia, paresthesia, and acute numbness of her left upper limb four weeks after the AstraZeneca COVID-19 vaccination. Laboratory data suggested hemolytic anemia and thrombocytopenia. Also, schistocytes were noted on her peripheral blood smear. Acquired thrombotic thrombocytopenic purpura (aTTP) was diagnosed in accordance with clinical manifestations along with initial blood test results and was confirmed later through findings of ADAMTS-13 low level activity and the ADAMTS-13 positive inhibitor. She underwent 22 sessions of plasma exchange, receiving corticosteroid and rituximab. Finally, the treatment was successful. Conclusion: Despite the presence of rare complications such as aTTP, vaccination is one of the best ways to prevent COVID-19 disease. The present case report describes the potential, but unproven, role of the AstraZeneca COVID-19 vaccine in aTTP pathogenesis. Vaccine-associated aTTP can be successfully treated with plasma exchange, corticosteroids, and rituximab.

Thrombotic thrombocytopenic purpura (TTP) after COVID-19 vaccination: A systematic review of reported cases.

INTRODUCTION: With the advent of COVID-19 vaccines, hospitalization rates and progression to severe COVID-19 disease have reduced drastically. Most of the adverse events reported by the vaccine recipients were minor. However, autoimmune hematological complications such as vaccine-induced immune thrombotic thrombocytopenia (VITT), immune thrombocytopenic purpura (ITP) and TTP have also been reported post-COVID-19 vaccination. Given this, we sought to reflect on the existing cases of TTP, whether de novo or relapsing, reported after COVID-19 vaccination to further gain insight into any association, if present, and outcomes. METHODS: We searched PubMed, Embase, and Ebsco databases for published individual case reports on the occurrence or relapse of TTP after receiving any COVID-19 vaccine. A total of 23 articles (27 patients) were included in this qualitative analysis. RESULTS: The mean age for the patients who developed de novo TTP post-COVID-19 vaccination was 51.3 years. TTP episodes were seen mostly after BNT162b2 vaccine, followed by mRNA-1273 vaccine. All patients with immune TTP except one received plasma exchange (PLEX) and steroids. One patient passed away after two days of hospitalization, likely due to a sudden cardiovascular event. CONCLUSION: Our review underscores the importance of in-depth anamnesis before vaccination and outlines characteristics of predisposed individuals. Evaluation of post-vaccine thrombocytopenia must include the possibility of TTP given the associated fatality with this condition.

COVID-19 vaccine (mRNA BNT162b2) and COVID-19 infection-induced thrombotic thrombocytopenic purpura in adolescents.

The mRNA COVID-19 vaccine and COVID-19 infection caused by the SARS-CoV-2 virus may be immunologic triggers for the development of thrombotic thrombocytopenic purpura (TTP). There is not yet literature that discusses TTP induced by COVID-19 vaccination or infection in pediatric or adolescent patients. We describe three adolescents presenting with TTP (both de novo and relapsed disease) following administration of the Pfizer COVID-19 vaccine or after COVID-19 infection. Our observations demonstrate that the Pfizer-BioNTech mRNA vaccine and COVID-19 infection can act as triggers for the development/relapse of both congenital and acquired TTP.

Trusted and Secure Blockchain-Based Durable Medium Electronic Service

A novel, trusted, and secure durable medium electronic service is proposed in the paper. The proposed idea joins cryptographic methods (such as signing with an electronic seal and data encryption) with blockchain techniques. The e-service and blockchain databases were implemented on the TTP side, which made the presented concept trusted and secure. The proposed electronic service was oriented towards practical implementations, and it has commonly been developed together with a company from the cybersecurity field (which is considered a TTP in the proposed approach). The concept has been designed to meet the requirements of Polish law (i.e., the conditions and regulations related to the implementation of the durable medium in Poland);nevertheless, it can easily be adapted for other regions. The functionality of the presented e-service is illustrated by the example case study.

Multiple Ischemic Strokes Due to Multisystem Inflammatory Syndrome in Adults (MIS-A).

Multisystem inflammatory syndrome in adults (MIS-A) is an extremely rare para-infectious or post-infectious complication of coronavirus disease 2019 (COVID-19) that requires prompt recognition and early treatment to avert severe morbidity and mortality. A 55-year-old woman presented to us with fever, multiple ischemic strokes, thrombocytopenia, elevated inflammatory markers, and multiorgan dysfunction a few days after COVID-19 illness. She was severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-negative at admission. MRI showed multiple posterior circulation infarctions. She required intensive treatment with intravenous methylprednisolone (IVMP), intravenous immunoglobulin (IVIg), sustained low-efficiency dialysis (SLED), and plasmapheresis for disease remission. Initially, her presentation raised concern for thrombotic thrombocytopenic purpura, however, many features raised the suspicion of a multisystem inflammatory syndrome in adults (MIS-A). Our patient had increased levels of D-dimer, fibrinogen, interleukin 6 (IL-6), and large artery thromboembolism, A positive direct Coomb's test was also more suggestive of immune-mediated hemolysis rather than traction hemolysis, which is the pathophysiology of hemolytic anemia in TTP. Furthermore, MIS-A is known to present with gastrointestinal (GI) symptoms, whereas our case reports predominantly neurological symptoms with relative GI sparing. The overall inflammatory milieu secondary to MIS-A would have contributed to the formation of immune thrombosis, which would have embolized up the vertebrobasilar tree. The MR angiogram did not show any atherosclerotic changes, ruling out an atherosclerotic etiology, which is quite common in posterior circulation infarctions. Multiple courses of immunomodulatory treatment and prolonged treatment with steroids led to disease stabilization.

Immune thrombotic thrombocytopenic purpura: Personalized therapy using ADAMTS-13 activity and autoantibodies.

Recently, treatment of immune-mediated thrombotic thrombocytopenic purpura (ITTP) has changed with the advent of caplacizumab in clinical practice. The International Working Group (IWG) has recently integrated the ADAMTS-13 activity/autoantibody monitoring in consensus outcome definitions. We report three ITTP cases during the coronavirus disease 2019 pandemic, that received a systematic evaluation of ADAMTS-13 activity and autoantibodies. We describe how the introduction of caplacizumab and ADAMTS-13 monitoring could change the management of ITTP patients and discuss whether therapeutic choices should be based on the clinical response alone. ADAMTS-13 activity/antibodies were assessed every 5 days. Responses were evaluated according to updated IWG outcome definitions. These kinetics, rather than clinical remission, guided the therapy, allowing early and safe caplacizumab discontinuation and sensible administration of rituximab. Caplacizumab was cautiously discontinued after achieving ADAMTS-13 complete remission. These cases illustrate that prospective ADAMTS-13 evaluation and use of updated IWG definitions may improve real-life patients' management in the caplacizumab era.

COVID-19-associated thrombotic angiopathy improved after plasma exchange.

Utilization of therapeutic plasma exchange in select patients with COVID-19 microangiopathy may provide useful treatment by modulation of inflammatory cytokines and coagulation cascade to maintain homeostasis.