Immunosuppressive drug combinations after kidney transplantation and post-transplant diabetes: A systematic review and meta-analysis.

Post-transplant diabetes mellitus (PTDM) is a frequent complication after kidney transplantation (KT). This systematic review investigated the effect of different immunosuppressive regimens on the risk of PTDM. We performed a systematic literature search in MEDLINE and CENTRAL for randomized controlled trials (RCTs) that included KT recipients with any immunosuppression and reported PTDM outcomes up to 1 October 2023. The analysis included 125 RCTs. We found no differences in PTDM risk within induction therapies. In de novo KT, there was an increased risk of developing PTDM with tacrolimus versus cyclosporin (RR 1.71, 95%CI [1.38-2.11]). No differences were observed between tacrolimus+mammalian target of rapamycin inhibitor (mTORi) and tacrolimus+MMF/MPA, but there was a tendency towards a higher risk of PTDM in the cyclosporin+mTORi group (RR 1.42, 95%CI [0.99-2.04]). Conversion from cyclosporin to an mTORi increased PTDM risk (RR 1.89, 95%CI [1.18-3.03]). De novo belatacept compared with a calcineurin inhibitor resulted in 50% lower risk of PTDM (RR 0.50, 95%CI [0.32-0.79]). Steroid avoidance resulted in 31% lower PTDM risk (RR 0.69, 95%CI [0.57-0.83]), whereas steroid withdrawal resulted in no differences. Immunosuppression should be decided on an individual basis, carefully weighing the risk of future PTDM and rejection.

International consensus on post-transplantation diabetes mellitus.

Post-transplantation diabetes mellitus (PTDM) remains a leading complication after solid organ transplantation. Previous international PTDM consensus meetings in 2003 and 2013 provided standardized frameworks to reduce heterogeneity in diagnosis, risk stratification and management. However, the last decade has seen significant advancements in our PTDM knowledge complemented by rapidly changing treatment algorithms for management of diabetes in the general population. In view of these developments, and to ensure reduced variation in clinical practice, a 3rd international PTDM Consensus Meeting was planned and held from 6-8 May 2022 in Vienna, Austria involving global delegates with PTDM expertise to update the previous reports. This update includes opinion statements concerning optimal diagnostic tools, recognition of prediabetes (impaired fasting glucose and/or impaired glucose tolerance), new mechanistic insights, immunosuppression modification, evidence-based strategies to prevent PTDM, treatment hierarchy for incorporating novel glucose-lowering agents and suggestions for the future direction of PTDM research to address unmet needs. Due to the paucity of good quality evidence, consensus meeting participants agreed that making GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) recommendations would be flawed. Although kidney-allograft centric, we suggest that these opinion statements can be appraised by the transplantation community for implementation across different solid organ transplant cohorts. Acknowledging the paucity of published literature, this report reflects consensus expert opinion. Attaining evidence is desirable to ensure establishment of optimized care for any solid organ transplant recipient at risk of, or who develops, PTDM as we strive to improve long-term outcomes.

Renal failure following insulin purging in atypical anorexia nervosa and type 1 diabetes mellitus.

Objective: Anorexia nervosa (AN) and atypical anorexia nervosa (AAN) are severe and complex eating disorders that can be prevalent among individuals with type 1 diabetes mellitus (T1DM). Insulin purging, characterized by the intentional underuse / omission of insulin to control weight, is under-recognized in medicine and is a purging strategy of patients with AN or AAN and comorbid T1DM. Often, this can lead to renal failure, necessitating a (pancreas-) kidney transplantation. This article presents a comprehensive overview of the interplay between AN/AAN and T1DM and summarizes the evidence in literature. Methods: A narrative review is presented on basis of a detailed case study of a 32-year-old female with end-stage renal failure seeking (pancreas-) kidney transplantation displaying etiology, diagnosis, comorbidities, complications, and treatment of AN and AAN with emphasis on those patients with T1DM. Results: Insulin purging in patients with AN/AAN and coexisting T1DM can exacerbate T1DM complications, including accelerating the onset of end-stage renal failure. A multidisciplinary approach including nutrition treatment and psychotherapeutic techniques was considered necessary for treatment, focusing on psychosomatic in-patient care before and after organ transplantation. Conclusion: Insulin purging in patients with AAN and T1DM poses severe health risks, including accelerated renal complications. For those considering transplantation, insulin purging has explicitly to be diagnosed and a holistic treatment addressing both the renal condition and psychosomatic symptoms/disorders is crucial for successful post-transplant outcomes.

Development and Validation of a New Score to Assess the Risk of Posttransplantation Diabetes Mellitus in Kidney Transplant Recipients.

Background: Posttransplantation diabetes mellitus (PTDM) is a serious complication of solid organ transplantation. It is associated with major adverse cardiovascular events, which are a leading cause of morbidity and mortality in transplant patients. This study aimed to develop and validate a score to predict the risk of PTDM in kidney transplant recipients. Methods: A single-center retrospective cohort study was conducted in a tertiary care hospital in Medellín, Colombia, between 2005 and 2019. Data from 727 kidney transplant recipients were used to develop a risk prediction model. Significant predictors with competing risks were identified using time-dependent Cox proportional hazard regression models. To build the prediction model, the score for each variable was weighted using calculated regression coefficients. External validation was performed using independent data, including 198 kidney transplant recipients from Tübingen, Germany. Results: Among the 727 kidney transplant recipients, 122 developed PTDM. The predictive model was based on 5 predictors (age, gender, body mass index, tacrolimus therapy, and transient posttransplantation hyperglycemia) and exhibited good predictive performance (C-index: 0.7 [95% confidence interval, 0.65-0.76]). The risk score, which included 33 patients with PTDM, was used as a validation data set. The results showed good discrimination (C-index: 0.72 [95% confidence interval, 0.62-0.84]). The Brier score and calibration plot demonstrated an acceptable fit capability in external validation. Conclusions: We proposed and validated a prognostic model to predict the risk of PTDM, which performed well in discrimination and calibration, and is a simple score for use and implementation by means of a nomogram for routine clinical application.

Standardized, risk-adapted induction therapy in kidney transplantation.

BACKGROUND: The choice of induction therapy in kidney transplantation is often non-standardized and centre-specific. Clinicians can choose between depleting and non-depleting antibodies, which differ in their immunosuppressive capacity and the concomitant risk of infection. We herein present a standardized risk-stratified algorithm for induction therapy that might help to balance the risk of rejection and/or serious infection. METHODS: Prior to kidney transplantation, patients were stratified into low-risk, intermediate-risk or high-risk according to our protocol based on immunologic risk factors. Depending on their individual immunologic risk, patients received basiliximab (low risk), antithymocyte globulin (intermediate risk) or low-dose alemtuzumab (high risk) for induction therapy. We analysed the results after 3 years of implementation of our risk-stratified induction therapy protocol at our kidney transplant centre. RESULTS: Between 01/2017 and 05/2020, 126 patients were stratified in accordance with our protocol (low risk/intermediate risk/high risk: 69 vs. 42 vs. 15 patients). The median follow-up time was 1.9 [1.0-2.5] years. No significant difference was observed in rejection rate and allograft survival (low risk/intermediate risk/high risk: 90.07% vs. 80.81% vs. 100% after 3 years (p > 0.05)) among the groups. The median eGFR at follow-up was (low risk/intermediate risk/high risk) 47 [33-58] vs 58 [46-76] vs 44 [22-55] ml/min/1.73 m2. Although the rate of viral and bacterial infections did not differ significantly, we observed a higher rate of opportunistic fungal infections with alemtuzumab induction. CONCLUSIONS: Our strategy offers facilitated and individualized choice of induction therapy in kidney transplantation. We propose further evaluation of our algorithm in prospective trials.

Impact of different immunosuppressive protocols on clinical outcomes in obese kidney transplant recipients: a propensity score-matched analysis.

BACKGROUND: Although obesity has become a significant problem in transplantation medicine, the impact of different immunosuppressive protocols on clinical outcomes in obese transplant recipients remains unclear. METHODS: We performed an analysis of the Scientific Registry of Transplant Recipients database. Kidney transplant recipients were categorized according to body mass index (BMI) categories and immunosuppressive protocols: (i) tacrolimus/mycophenolate mofetil (Tac-MMF), (ii) mTOR-inhibitor/Tac (mTORi-Tac), (iii) mTORi/cyclosporin (mTORi-Cyc) and (iv) mTORi-MMF. RESULTS: Graft recipients with advanced obesity (BMI ≥35 kg/m2) exhibited significantly lower rates of acute rejection during the first year after transplantation in the mTORi-Tac (6.4%) group compared with Tac-MMF (11.2%). Obesity class 1 (30 < BMI < 35 kg/m2) was associated with a significant risk of acute rejection for the mTORi-Tac group [obesity class 1 hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.21-2.62, P = .003]. A similar trend was observed in the Tac-MMF group for advanced obesity HR 1.29; 95% CI 0.96-1.73, P = .087). For the Tac-MMF group, recipients with both overweight and obesity had significantly impaired survival due to cardiovascular events and also increased mortality due to infection in advanced obesity. Combination of mTORi and calcineurin inhibitor was associated with lower rejection rates and stable long-term kidney function while reducing cardiovascular side effects linked to calcineurin inhibitors in obese kidney graft recipients. CONCLUSION: These results are critical for the growing number of obese graft recipients and warrant prospective evaluation.

Functional MRI to quantify perfusion changes of a renal allograft after embolization of an arteriovenous fistula.

Acute allograft injury was observed in a 37-year-old woman within a few weeks after kidney transplantation. Neither renal ultrasound nor computerized tomography (CT) and magnetic resonance (MR) angiography revealed any anomaly. An MR protocol was then performed including arterial spin labeling and intravoxel incoherent motion diffusion weighted imaging. Both arterial spin labeling and the perfusion fraction in the diffusion weighted imaging showed decreased perfusion compared to reference values. The patient subsequently underwent angiography, where an arteriovenous fistula in the upper calix of the transplant kidney was detected and immediate embolization was performed. A second functional MR, performed one week later, demonstrated a 40% increase in organ perfusion. We conclude that functional MR with arterial spin labeling and intravoxel incoherent motion have the potential to provide complementary information of clinical value to conventional imaging for monitoring renal allografts.

Immune Checkpoint Inhibitors in Solid Organ Transplant Recipients With Advanced Skin Cancers-Emerging Strategies for Clinical Management.

Use of immune checkpoint inhibitors (ICIs) in solid organ transplant recipients (SOTRs) with advanced skin cancers presents a significant clinical management dilemma. SOTRs and other immunosuppressed patients have been routinely excluded from ICI clinical trials with good reason: immune checkpoints play an important role in self- and allograft-tolerance and risk of acute allograft rejection reported in retrospective studies affects 10% to 65% of cases. These reports also confirm that cutaneous squamous cell carcinoma and melanoma respond to ICI therapy, although response rates are generally lower than those observed in immunocompetent populations. Prospective trials are now of critical importance in further establishing ICI efficacy and safety. However, based on current knowledge, we recommend that ICIs should be offered to kidney transplant recipients with advanced cutaneous squamous cell carcinoma, melanoma, or Merkel cell carcinoma if surgery and/or radiotherapy have failed. For kidney transplant recipients, this should be first line ahead of chemotherapy and targeted therapies. In SOTRs, the use of ICIs should be carefully considered with the benefits of ICIs versus risks of allograft rejection weighed up on a case-by-case basis as part of shared decision-making with patients. In all cases, parallel management of immunosuppression may be key to ICI responsiveness. We recommend maintaining immunosuppression before ICI initiation with a dual immunosuppressive regimen combining mammalian target of rapamycin inhibitors and either corticosteroids or calcineurin inhibitors. Such modification of immunosuppression must be considered in the context of allograft risk (both rejection and also its subsequent treatment) and risk of tumor progression. Ultimately, a multidisciplinary approach should underpin all clinical decision-making in this challenging scenario.

Uterine allograft removal by total laparoscopic hysterectomy after successful cesarean delivery in a living-donor uterus recipient with uterovaginal agenesis (MRKHS).

PURPOSE: To limit the burden of long-term immunosuppression (IS) after uterus transplantation (UTx), removal of the uterine allograft is indicated after maximum two pregnancies. Hitherto this has required graft hysterectomy by laparotomy. Our objective was to demonstrate, as a proof of concept, the feasibility of less traumatic transplantectomy by total laparoscopic hysterectomy (TLH). PATIENT: A 37-year-old woman with uterovaginal agenesis due to Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) who had undergone neovaginoplasty at age 19 years prior to living-donor (LD) UTx in 10/2019 at age 35 years gave birth to a healthy boy by primary cesarean section in 06/2021. During pregnancy, she developed impaired renal function, with bilateral hydronephrosis, necessitating early allograft removal in 09/2021 to prevent chronic kidney disease, particularly during a potential second pregnancy. METHODS: Transplantectomy by TLH essentially followed standard TLH procedures. We paid meticulous attention to removing as much donor tissue as possible to prevent postoperative complications from residual donor tissue after stopping IS, as well as long-term vascular damage. RESULTS: TLH was performed successfully without the need to convert to open surgery. Surgical time was 90 min with minimal blood loss. No major complications occurred intra- or postoperatively and during the subsequent 9-month follow-up period. Kidney function normalized. CONCLUSIONS: To our knowledge, we report the first successful TLH-based removal of a uterine allograft in a primipara after LD UTx, thus demonstrating the feasibility of TLH in uterus recipients with MRKHS.

Living kidney donor evaluation is associated with early identification of life-changing diagnoses in potentially healthy donor candidates.

BACKGROUND: In order to ensure eligibility for living kidney donation, donor candidates undergo a thorough medical evaluation. This process might reveal hitherto undetected medical conditions, leading to refusal of the kidney donor candidate. Detection of such conditions may, however, also have a lifesaving effect. We report on 13 years of data from our living donor transplantation program on kidney donor candidates who were diagnosed with major medical conditions during evaluation. MATERIALS AND METHODS: We performed a retrospective analysis of living kidney donor candidates who attended our transplant center between January, 2007 and December, 2019. The main focus was on newly diagnosed medical conditions that required immediate medical attention and their prognostic significance. RESULTS: Of the 436 donor candidates who were evaluated for living kidney donation at our transplant center, 192 (44%) were accepted, while 244 (56%) were excluded from donation. Interestingly, 81 (33.1%) of the ineligible donor candidates were newly diagnosed as having a medical condition that required immediate attention. While 45 (18.5%) candidates were newly diagnosed with diabetes or prediabetes, 12 (4.9%) candidates had hitherto undetected malignancies, 10 candidates (4.1%) cardiac disease, five (2.0%) hypertension with end-organ damage, and four (1.6%) suffered from kidney disease. The remaining four candidates (1.6%) were diagnosed with gastrointestinal diseases, and one candidate (.4%) had an endocrine disorder. CONCLUSION: A comprehensive evaluation process for living kidney donation facilitates the identification of life-changing diagnoses in a significant proportion of candidates and secures immediate medical attention.

Late Onset Cerebral Nocardiosis in a Sensitized Renal Transplant Recipient Following Alemtuzumab Induction: A Case Report.

BACKGROUND: Balancing immunosuppressive regimen to prevent rejection yet avoiding severe infectious complications remains a key challenge following renal transplantation, especially in patients sensitized after exposure to human leukocyte antigens. We herein report a late onset infection with nocardia in a sensitized renal transplant recipient. CASE PRESENTATION: A 65-year-old male patient, who had received kidney transplantation with alemtuzumab induction due to human leukocyte antigen-sensitization 3 years ago, was admitted with headache and dizziness. A cerebral magnetic resonance imaging scan showed a right parieto-occipital brain abscess. Surgical abscess drainage was performed and microbiology analysis detected Nocardia paucivorans in the abscess fluid. Laboratory results showed persistently reduced lymphocyte and T-cell counts 3 years after transplantation. We started intravenous antibiotic therapy with high dose trimethoprim/sulfamethoxazole and imipenem/cilastatin. Furthermore, immunosuppression was adapted with discontinuation of mycophenolate. After 7 weeks of intravenous antibiotic therapy, the patient was switched to an oral antibiotic regimen with amoxicillin/clavulanic acid and minocycline. In the follow-up magnetic resonance imaging scan, cerebral lesions were substantially reduced, initial symptoms completely disappeared, and allograft function remained stable. CONCLUSIONS: Induction therapy with the CD52-antibody alemtuzumab enables transplantation in highly sensitized patients but leads to lymphocyte depletion for several weeks. Our patient presented with prolonged lymphopenia and a significantly reduced T-cell count 3 years after transplantation. To our knowledge, our case is the first to describe a late-onset nocardia infection 3 years after alemtuzumab induction in a renal transplant recipient. It underlines the importance of considering this rare disease in transplant patients, especially after induction therapy with depleting antibodies.

[SARS-CoV-2 Infections and Clinical Consequences in a Cohort of Solid Organ Transplant Recipients during the first Wave in Germany - a Single Centre Survey and a Case Report]. / SARS-CoV-2-Infektionen und klinische Konsequenzen bei organtransplantierten Patienten im Rahmen der ersten Ansteckungswelle in Deutschland - eine monozentrische Umfrage und ein Fallbericht.

BACKGROUND: The SARS-CoV-2 pandemic has caused an unprecedented global health crisis, with exceptionally high mortality rates in high-risk groups of affected patients. It is alarming that a steadily increasing number of clinical reports on outcomes of COVID-19 in solid organ transplant (SOT) recipients suggests a detrimental impact linked to high overall mortality. However, systematic data on SARS-CoV-2 infections in SOT recipients in Germany are still scarce. MATERIAL AND METHODS: We conducted a survey on SARS-CoV-2 infection status among 387 SOT recipients treated at our centre during the past 5 years - located in a severely affected region in Germany. The survey was sent out two months after the first SARS CoV-2 outbreak in our region had resulted in government-imposed lockdown measures. RESULTS: An incidence rate of 0.4% SARS-CoV-2-positive SOT recipients was determined in our cohort, in line with reported local infection rates in the general population at this time. However, the only SARS CoV-2 infection known to us within this group of patients led to severe morbidity - resulting in prolonged mechanical ventilation, hospitalisation > 60 days and finally in irreversible loss of graft function. CONCLUSION: Our data demonstrate that SOT recipients are at equal risk for SARS-CoV-2 infections when compared to the general population, while SARS-CoV-2 infections in SOT recipients seem to be associated with deleterious clinical consequences.

SARS-CoV-2 in Solid Organ Transplant Recipients: A Structured Review of 2020.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is challenging health systems all over the world. Particularly high-risk groups show considerable mortality rates after infection. In 2020, a huge number of case reports, case series, and consecutively various systematic reviews have been published reporting on morbidity and mortality risk connected with SARS-CoV-2 in solid organ transplant (SOT) recipients. However, this vast array of publications resulted in an increasing complexity of the field, overwhelming even for the expert reader. METHODS: We performed a structured literature review comprising electronic databases, transplant journals, and literature from previous systematic reviews covering the entire year 2020. From 164 included articles, we identified 3451 cases of SARS-CoV-2-infected SOT recipients. RESULTS: Infections resulted in a hospitalization rate of 84% and 24% intensive care unit admissions in the included patients. Whereas 53.6% of patients were reported to have recovered, cross-sectional overall mortality reported after coronavirus disease 2019 (COVID-19) was at 21.1%. Synoptic data concerning immunosuppressive medication attested to the reduction or withdrawal of antimetabolites (81.9%) and calcineurin inhibitors (48.9%) as a frequent adjustment. In contrast, steroids were reported to be increased in 46.8% of SOT recipients. CONCLUSIONS: COVID-19 in SOT recipients is associated with high morbidity and mortality worldwide. Conforming with current guidelines, modifications of immunosuppressive therapies mostly comprised a reduction or withdrawal of antimetabolites and calcineurin inhibitors, while frequently maintaining or even increasing steroids. Here, we provide an accessible overview to the topic and synoptic estimates of expectable outcomes regarding in-hospital mortality of SOT recipients with COVID-19.

Contrast-enhanced MRI for simultaneous evaluation of renal morphology and split renal function in living kidney donor candidates.

PURPOSE: The evaluation process of potential living kidney donors focusses on renal anatomy and split renal function. This study aimed to evaluate a magnetic resonance imaging (MRI)-based approach for simultaneous evaluation of both and its impact on clinical decision making. METHOD: Over a 3-year period, 65 potential living kidney donors were consecutively enrolled. The MRI protocol was extended by MR-nephrography to measure split renal function. Standard DTPA-scintigraphy was used for functional comparison. RESULTS: Split renal function showed no systematic bias between the two methods (mean difference 0.3%, p = 0.08). Both methods would have yielded the same clinical decision for donor nephrectomy in 75% of the patients. In 25 % of the patients, one method indicated a relevant side difference while the other did not, and a different clinical decision could have been made based on split renal function alone. CONCLUSIONS: MRI proved eligible for comprehensive living kidney donor evaluation and non-inferior to scintigraphy for determining split renal function. In clinical decision making, these two methods would have resulted in the same side for donor nephrectomy in a large proportion of potential donors. Whether MRN will be implemented in clinical practice depends on transplant centre infrastructure and policy.

Dynamics of glucose metabolism after liver transplantation: prediabetes as a window of opportunity for patient survival and long-term kidney function.

Post-transplantation diabetes mellitus (PTDM) is a relevant complication following liver transplantation with profound impact on morbidity and mortality. To date, little is known about the evolution and dynamics of glucose metabolism and the impact of prediabetes in long-term follow-up. To address this issue, all consecutive adult liver transplant recipients (n = 429) from a European university hospital transplant center between 2007 and 2017 were analyzed retrospectively. In patients without pre-existing diabetes (n = 327), we conducted a longitudinal characterization of glucose metabolism. Median follow-up was 37 [9-64, IQR] months. Median prevalence of prediabetes was 39 [37-39]% and of PTDM 21 [17-22]%. Throughout follow-up, intra-individual glucose regulation of patients was highly variable, continuously fluctuating between different states of glucose metabolism (normal glucose tolerance, prediabetes, PTDM). Whereas overall survival and long-term kidney function of patients with PTDM were significantly lower than that of patients with normal glucose metabolism, prediabetes was not associated with adverse outcome. This study provides new insight into the dynamics and impact of glucose metabolism after liver transplantation. Unlike PTDM, prediabetes is not associated with adverse outcome, providing a window of opportunity for targeted intervention. The results underline the need for constant screening and intervention in posttransplant care of liver allograft recipients.

Successful long-term management of recurrent focal segmental glomerulosclerosis after kidney transplantation with costimulation blockade.

Recurrence of primary focal segmental glomerulosclerosis (FSGS) occurs in up to 50% of patients after kidney transplantation and is associated with poor allograft outcome. Novel therapeutic concepts directly target podocyte function via B7-1 with inconsistent response. We present the case of a 19-year-old patient with recurrent primary FSGS early after living donor kidney transplantation. Plasmapheresis and rituximab did not induce remission. Repetitive abatacept administration was able to achieve partial remission. Maintenance immunosuppression was subsequently switched to a belatacept-based calcineurin inhibitor-free immunosuppression, resulting in sustained complete remission with excellent allograft function throughout a follow-up of >56 months.

Antibody-mediated procoagulant platelets in SARS-CoV-2-vaccination associated immune thrombotic thrombocytopenia.

The COVID-19 pandemic has resulted in significant morbidity and mortality worldwide. To prevent severe infection, mass COVID-19 vaccination campaigns with several vaccine types are currently underway. We report pathological and immunological findings in 8 patients who developed vaccine-induced immune thrombotic thrombocytopenia (VITT) after administration of SARS-CoV-2 vaccine ChAdOx1 nCoV-19. We analyzed patient material using enzyme immune assays, flow cytometry and heparin-induced platelet aggregation assay and performed autopsies on two fatal cases. Eight patients (5 female, 3 male) with a median age of 41.5 years (range, 24 to 53) were referred to us with suspected thrombotic complications 6 to 20 days after ChAdOx1 nCoV-19 vaccination. All patients had thrombocytopenia at admission. Patients had a median platelet count of 46.5 x109/L (range, 8 to 92). Three had a fatal outcome and 5 were successfully treated. Autopsies showed arterial and venous thromboses in various organs and the occlusion of glomerular capillaries by hyaline thrombi. Sera from VITT patients contain high titer antibodies against platelet factor 4 (PF4) (OD 2.59±0.64). PF4 antibodies in VITT patients induced significant increase in procoagulant markers (P-selectin and phosphatidylserine externalization) compared to healthy volunteers and healthy vaccinated volunteers. The generation of procoagulant platelets was PF4 and heparin dependent. We demonstrate the contribution of antibody-mediated platelet activation in the pathogenesis of VITT.