ADAMTS13 Activity Research Articles

ADAMTS13活性のアロステリック調節

ADAMTS13はvon Willebrand factor（VWF）を特異的に切断するメタロプロテアーゼである．ADAMTS13のVWF切断活性は自身のコンフォメーション変化をともなうアロステリックな機構により調節されている．遊離状態のADAMTS13は，スペーサー（S）ドメインにC末端の2つのCUBドメインが結合し，ヘアピン様の閉じたコンフォメーションとなって活性が抑制されている．ADAMTS13のCUBドメインを含むC末端側領域がVWFのC末端側のD4～CK領域に結合すると，CUBドメインはSドメインから外れ，ADAMTS13は開いたコンフォメーションとなる．この時，ADAMTS13のN末端側領域は，ずり応力で伸びたVWF A2ドメインに結合し，VWFを切断する．ADAMTS13のコンフォメーション状態が血栓性血小板減少性紫斑病の発症や病態と関連していることも明らかになった．

Prognostic value of the ADAMTS13-vWF axis in disseminated intravascular coagulation: Platelet count/vWF:Ag ratio as a strong prognostic marker.

ADAMTS13 deficiency increases the circulating level of von Willebrand factor (vWF). Low ADAMTS13 and high vWF can provide a milieu for microthrombosis, including disseminated intravascular coagulation (DIC). This study investigated the prognostic values of ADAMTS13-vWF axis markers and their correlation with DIC severity. ADAMTS13-vWF axis markers (vWF antigen (vWF:Ag), vWF ristocetin cofactor (vWF:Rco), ADAMTS13 activity, and anti-ADAMTS13 antibody) were measured in patients (n=152) suspected of having DIC along with the well-known DIC markers including antithrombin and protein C. The vWF:Ag level was significantly increased, and ADAMTS13 activity was significantly decreased in overt DIC. The vWF:Ag level (hazard ratio 7.365, p=.009), ADAMTS13 activity/vWF:Ag ratio (hazard ratio 3.777, p=.037), ADAMTS13 activity/vWF:Rco ratio (hazard ratio 3.027, p=.028), and platelet count/vWF:Ag ratio (hazard ratio 8.538, p<.001) were significant prognostic markers in Cox regression analysis and correlated well with DIC score and antithrombin and protein C levels. The platelet count/vWF:Ag was the strongest prognostic marker among ADAMTS13-vWF axis markers. The measurement of vWF:Ag may improve prognostic insights of DIC in clinical practice.

Reduced cleavage of von willebrand factor by ADAMTS13 is associated with microangiopathic acute kidney injury following trauma.

Acute kidney injury (AKI) is common after trauma, but contributory factors are incompletely understood. Increases in plasma von Willebrand Factor (vWF) with concurrent decreases in ADAMTS13 are associated with renal microvascular thrombosis in other disease states, but similar findings have not been shown in trauma. We hypothesized that molecular changes in circulating vWF and ADAMTS13 promote AKI following traumatic injury. VWF antigen, vWF multimer composition and ADAMTS13 levels were compared in plasma samples from 16 trauma patients with and without trauma-induced AKI, obtained from the Prehospital Air Medical Plasma (PAMPer) biorepository. Renal histopathology and function, vWF and ADAMTS13 levels were assessed in parallel in a murine model of polytrauma and haemorrhage. VWF antigen was higher in trauma patients when compared with healthy controls [314% (253–349) vs. 100% (87–117)] [median (IQR)], while ADAMTS13 activity was lower [36.0% (30.1–44.7) vs. 100.0% (83.1–121.0)]. Patients who developed AKI showed significantly higher levels of high molecular weight multimeric vWF at 72-h when compared with non-AKI counterparts [32.9% (30.4–35.3) vs. 27.8% (24.6–30.8)]. Murine plasma cystatin C and vWF were elevated postpolytrauma model in mice, with associated decreases in ADAMTS13, and immunohistologic analysis demonstrated renal injury with small vessel plugs positive for fibrinogen and vWF. Following traumatic injury, the vWF-ADAMTS13 axis shifted towards a prothrombotic state in both trauma patients and a murine model. We further demonstrated that vWF-containing, microangiopathic deposits were concurrently produced as the prothrombotic changes were sustained during the days following trauma, potentially contributing to AKI development.

Pregnancy onset congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) mimicking HELLP syndrome: a case report

Objective Thrombotic thrombocytopenic purpura is a thrombotic microangiopathic condition characterized by hemolytic anemia, thrombocytopenia, neurologic abnormalities, fever and renal dysfunction. Thrombotic microangiopathies such as preeclampsia and HELLP syndrome are pregnancy-specific, whereas others such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome are not. In this report, we present a case at which we identified a novel mutation which led to a significant reduction of ADAMTS13 activity. Case(s) A nulliparous pregnant woman of 32-year-old presenting with epigastric pain, hypertension and low platelet count was first suspected of HELLP syndrome, but was diagnosed with congenital TTP after delivery. Conclusion HELLP syndrome co-existed with undiagnosed TTP in this case. We strive to have sufficient awareness in order to distinguish these two pathologies from each other on an antenatal basis, because the causes of the managements are entirely different.

First diagnosis of thrombotic thrombocytopenic purpura after SARS-CoV-2 vaccine \u2013 case report

BackgroundWe report a case of a 25-year-old male patient, who developed acquired thrombotic thrombocytopenic purpura (aTTP) after receiving a first dose of mRNA-based SARS-CoV-2 vaccine Spikevax (mRNA-1273, Moderna Biotech, USA). While this is the first case in literature describing a case of aTTP after receiving the Spikevax vaccine, there are two other cases after mRNA-based Covid-19 vaccine and two after adenoviral SARS-CoV-2 vaccine.Case presentationThe patient presented with persisting malaise, fever, headache, word-finding difficulties, nausea, vomiting, petechial bleeding, and hematuria 13 days after receiving a first dose of vaccination. Laboratory testing showed low platelet count, Coombs-negative hemolytic anemia, and mild acute kidney injury. We excluded vaccine induced immune thrombotic thrombocytopenia (VITT) as another important differential diagnosis and the final diagnosis was established after ADAMTS-13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) activity was found to be < 1% (reference range > 40%) and ADAMTS-13 antibodies being 72.2 IU/L (reference range < 12 IU/L).We initiated empiric therapy of plasmapheresis and corticosteroids on admission and started caplacizumab the day after. The patient’s thrombocyte count normalized 3 days after admission, hemolysis and acute kidney injury resolved after 2 weeks. The patient received 2 doses of rituximab (1 g each) after the diagnosis of immune TTP was established. One month after the initial presentation, the patient is in good overall condition, but still receives daily caplacizumab due to ADAMTS-13 activity of < 1%.ConclusionsLow platelet count after vaccination against SARS-CoV-2 has gained attraction after vaccine-induced immune thrombotic thrombocytopenia (VITT) has been described as a rare but severe complication of adenoviral-based vaccines. Thrombotic thrombocytopenic purpura (TTP) is an important differential diagnosis, but there are only few reports of TTP following SARS-CoV-2 vaccination. Despite pathophysiological and clinical differences of both entities, diagnostic uncertainty can result in the acute setting, since they share main symptoms such as headache and neurological alterations in addition to thrombocytopenia. In difference to other cases reported, this patient developed first symptoms of TTP as early as 4 days after vaccination, which suggests that vaccination merely acted as trigger for occult TTP, instead of truly inducing an autoimmunological process.

Case series: coronavirus disease 2019 infection as a precipitant of atypical hemolytic uremic syndrome: two case reports

BackgroundAtypical hemolytic uremic syndrome is an exceedingly rare thrombotic microangiopathy caused by accelerated activation of the alternative complement pathway.Case presentationHere, we report two cases of patients presenting with suspected atypical hemolytic uremic syndrome precipitated by coronavirus disease 2019 infection. The first patient, a 25-year-old Hispanic male, had one prior episode of thrombotic microangiopathy presumed to be atypical hemolytic uremic syndrome precipitated by influenza A, and re-presented with thrombocytopenia, microangiopathic hemolytic anemia, nonoliguric renal failure, and normal ADAMTS13 activity, with confirmed coronavirus disease 2019 positivity. The second patient, a 31-year-old Caucasian female, had no personal history of thrombotic microangiopathy, though reported a family history of suspected atypical hemolytic uremic syndrome. She presented with similar laboratory derangements, oliguric renal failure requiring hemodialysis, and confirmed coronavirus disease 2019 positivity. Both patients were treated with eculizumab with complete resolution of their hematologic and renal complications.ConclusionTo our knowledge, this represents the largest case series of atypical hemolytic uremic syndrome precipitated by coronavirus disease 2019 in adults.

Robust thrombolytic and anti-inflammatory action of a constitutively active ADAMTS13 variant in murine stroke models

AbstractAdvances in our understanding of ADAMTS13 structure, and the conformation changes required for full activity, have rejuvenated the possibility of its use as a thrombolytic therapy. We have tested a novel Ala1144Val ADAMTS13 variant (constitutively active [ca] ADAMTS13) that exhibits constitutive activity, characterized using in vitro assays of ADAMTS13 activity, and greatly enhanced thrombolytic activity in 2 murine models of ischemic stroke, the distal FeCl3 middle cerebral artery occlusion (MCAo) model and transient middle cerebral artery occlusion (tMCAO) with systemic inflammation and ischemia/reperfusion injury. The primary measure of efficacy in both models was restoration of regional cerebral blood flow (rCBF) to the MCA territory, which was determined using laser speckle contrast imaging. The caADAMTS13 variant exhibited a constitutively active conformation and a fivefold enhanced activity against fluorescence resonance energy transfer substrate von Willebrand factor 73 (FRETS-VWF73) compared with wild-type (wt) ADAMTS13. Moreover, caADAMTS13 inhibited VWF-mediated platelet capture at subphysiological concentrations and enhanced t-PA/plasmin lysis of fibrin(ogen), neither of which were observed with wtADAMTS13. Significant restoration of rCBF and reduced lesion volume was observed in animals treated with caADAMTS13. When administered 1 hour after FeCl3 MCAo, the caADAMTS13 variant significantly reduced residual VWF and fibrin deposits in the MCA, platelet aggregate formation, and neutrophil recruitment. When administered 4 hours after reperfusion in the tMCAo model, the caADAMTS13 variant induced a significant dissolution of platelet aggregates and a reduction in the resulting tissue hypoperfusion. The caADAMTS13 variant represents a potentially viable therapeutic option for the treatment of acute ischemic stroke, among other thrombotic indications, due to its enhanced in vitro and in vivo activities that result from its constitutively active conformation.

Abstract 12602: Local NET Burden is Associated With Biomarkers of Thrombosis and Cardiac Damage in Left Atrial Cardiopathy

Atrial cardiopathy results in disturbed blood flow, providing an ideal thrombogenic environment. Neutrophils promote large vessel occlusions and microthrombosis via release of neutrophil extracellular traps (NETs) and thus lie at the interface of (sterile) inflammation, thrombosis, and fibrosis. We profiled NETs, cytokines, thrombotic factors, and cardiac damage markers in left atrial (LA) cardiopathies together with LA structural analysis. A total of 71 patients (median age 66, 46.5% male) undergoing catheterization procedures with atrial transseptal access at the Freiburg Heart Center were enrolled in this prospective study. Paired samples were collected from peripheral blood draws or from within the left atrium (LA). NET biomarkers, sP-selectin, PAD4, proinflammatory cytokines, thrombotic factors (D-dimers, VWF, ADAMTS13), and cardiac damage markers (TropT, proBNP, ICTP) were measured in plasma or serum as appropriate. Echocardiography was performed to assess LA structure and left ventricular function. Data were analyzed by the type of procedure (MitraClip (MC), left atrial appendage closure (LAAC), pulmonary vein ablation (PVA), or patent foramen ovale closure (PFOC), and by atrial fibrillation (Afib) status at time of procedure. NETs, but not other markers, were elevated in local LA samples as compared to peripheral blood. Conversely, most thrombotic, inflammatory, and cardiac damage markers, but not NETs, were elevated in MC or LAAC as compared to PFOC or PVA patients. Across all patients, NET biomarkers positively correlated with IL-6/TNF-α, VWF, and cardiac damage biomarkers. PAD4/NETs negatively correlated with ADAMTS13 activity, indicating that citrullination may contribute to the prothrombotic phenotype of these patients. Afib was not key to these observations. NETs are locally elevated within the left atrium, with elevation of thrombosis markers including VWF in patients with a diseased left atrium. These elevations partly correlate with structural changes of the left atrium and, therefore, may point toward a disturbed local blood flow. This may provide insight on mechanisms that drive detrimental left atrial remodeling as well as clues regarding thromboembolic risks that are rooted in LA changes rather than Afib.

Abstract 12399: Don’t Burst My Blood: Ticagrelor Induced Thrombotic Thrombocytopenic Purpura

Background: Dual antiplatelet therapy, a fundamental component of the treatment of acute coronary syndromes (ACS), increases bleeding risk. Patients with thrombocytopenia and ACS are difficult to manage as thrombocytopenia increases the risk both of bleeding and ischemic events. Case: A 47 year old male with a medical history most significant for coronary artery disease (requiring multiple stents) and stroke who presented with chest pain and was found to have a NSTEMI. Notably, the patient stopped his ticagrelor six weeks prior to presentation. The initial CBC demonstrated clumped platelets. The patient was loaded with aspirin and ticagrelor, placed on a heparin drip and admitted. Decision Making: Exam on the morning after presentation demonstrated jaundice as well as petechiae on the patient’s extremities. He then exhibited altered mental status concerning for a seizure. Repeat labs demonstrated new severe thrombocytopenia, confirmed on a dedicated platelet count, anemia and indirect hyperbilirubinemia. A peripheral smear did not demonstrate schistocytes; however, the PLASMIC score indicated a high risk of thrombotic thrombocytopenic purpura (TTP) and he was started on plasmapheresis and steroids. His ADAMTS13 activity level returned low, confirming TTP. Common causes of TTP were excluded and Ticagrelor was deemed responsible. With continued plasmapheresis and steroids, his platelets normalized. A diagnostic left heart catheterization demonstrated patent prior stents as well as a 90% mid circumflex lesion. The patient was discharged on aspirin and rivaroxaban per the COMPASS trial, and was advised to avoid further P2Y12 inhibitors. Conclusion: This case demonstrated ticagrelor induced TTP, which has been infrequently reported in the literature. The patient was likely previously sensitized to ticagrelor and then developed TTP when he was loaded on presentation. It also demonstrates the importance of not ignoring clumped platelets and obtaining a true platelet count prior to starting triple therapy. In normal circumstances, his circumflex lesion would likely have been intervened upon; however, the patient’s intolerance of P2Y12 inhibitors limited management options during this presentation and will likely limit future interventions.

High levels of Von Willebrand factor markers in COVID-19: a systematic review and meta-analysis.

The SARS-CoV-2 virus has spread to all corners of the world. Thrombosis is the cause of organ failure and subsequent death in COVID-19. The pathophysiology of thrombosis in COVID-19 needs to be further explored to shed light on its downside. For this reason, this meta-analysis of Von Willebrand Factor profile (VWF: Ag, VWF: activity, VWF: RCo), ADAMTS-13, and factor VIII levels in COVID-19 was performed. To obtain data on the status of the aforementioned hemostatic factors, a systematic literature review and meta-analysis were performed on COVID-19. After reviewing the evaluation of 348 papers, 28 papers included in the meta-analysis, which was performed using STATA. The analysis showed an increase in VWF: Ag levels in COVID‐19 patients. VWF: Ac was higher in all COVID-19 patients, while it was lower in the COVID‐19 ICU patients. The pooled mean of VWF: RCO in all patients with COVID-19 was 307.94%. In subgroup analysis, VWF: RCO was significantly higher in ICU patients than in all COVID-19 patients. The pooled mean of ADAMTS-13 activity was 62.47%, and 58.42% in ICU patients. The pooled mean of factor VIII level was 275.8%, which was significantly higher in ICU patients with COVID-19 than all patients with COVID-19. Levels of VWF: Ag, VWF: activity, VWF: ristocetin, and factor VIII are increased in patients with COVID-19. The elevated levels in ICU patients with COVID-19 suggest that these markers may have prognostic value in determining the severity of COVID-19. New therapeutic programs can be developed as a result.

Evaluating Patterns in ADAMTS13 Testing and Time to Plasma Exchange Initiation for Suspected Thrombotic Thrombocytopenic Purpura at a County Hospital

Introduction: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening disease with a mortality 10-20% despite emergent therapeutic plasma exchange (TPE). The distinguishing aspect of iTTP from other thrombotic microangiopathies is a severe deficiency of ADAMTS13 (<10% activity) with laboratory evaluation of ADAMTS13 activity often requiring hours to days; thus, it is not useful for determining whether plasma exchange for TTP should be initiated. Guidelines also recommend TPE initiation within 4-8 hours (Scully 2012). There is limited literature regarding utilization of ADAMTS13 testing in the hospital, and we sought to understand ordering patterns in various clinical contexts, which services ordered ADAMTS13 activity, and if TPE initiation was timely.Methods: Parkland Health and Hospital System records were reviewed ADAMTS13 activity tests (n = 361) from January 2019 to March 2021, excluding patients with known iTTP and/or outpatient tests; resulting in a final cohort of 42 patients with inpatient ADAMTS13 activity tests for suspected iTTP. Suspicion for iTTP-time zero for our time to TPE analysis-was determined by the time that the ADAMTS13 order was placed. Hematology consultation time was based on when the order was placed by the provider. The initiation of TPE, as documented by the apheresis team, was the end-time for the time to TPE calculation. Thus, time to TPE was the time elapsed between the electronic ADAMTS13 order being placed and TPE being initiated.Results: The median patient age was 43 years with 36% Black patients and 50% Hispanic. Hematology service consultation occurred in 95% of cases, although only 79% of hematology consultations occurred before ADAMTS13 activity orders were placed (Table 1). The most common services to order an ADAMTS13 activity prior to hematology consultation were obstetrics and gynecology (2/2, 100%), neurology (1/1, 100%), and medical intensive care (5/14, 36%) with 88% of these tests being placed for patients with a PLASMIC score ≤ 4. None of these patients were diagnosed with iTTP. Using a PLASMIC score ≥6 as a diagnostic test for iTTP, the sensitivity was 50%, specificity 84%, positive predictive value 20%, and negative predictive value was 94%.A subgroup analysis of patients empirically treated for iTTP (n = 7) demonstrated a wide variation in the time from ADAMTS13 activity orders being placed to initiation of TPE, ranging from 4 hours 44 minutes to 3 days 14 hours (Table 2). Only one patient (without a pre-existing central line) received empiric TPE in under 6 hours (5 hours and 20 minutes). One patient had an ADAMTS13 activity that resulted with a critical ADAMTS13 deficiency and was initiated on TPE; this level was re-analyzed, found to be spurious, and the TPE was ceased immediately. No patients received empiric plasma transfusion.Discussion: At our county, public hospital, 95% of cases with suspected iTTP involved hematology consultation during their evaluation, but the most common situations where hematology was not involved at all or was involved late were due to non-internal medicine services, identifying areas for focused educational interventions. The PLASMIC score demonstrated insufficient sensitivity (50%) to confidently exclude iTTP, suggesting that it is an inadequate risk stratification tool for our specific patient population. This may be due to differences between our patient population (with a median age of 43 and 12% white patients) and the derivation cohort for the PLASMIC score (with a median age of 51 and 77% white patients; Bendapudi 2017). The finding that only one patient without a pre-existing central line received TPE in ≤6 hours suggests that there is room for quality improvement interventions to hasten time to treatment. This initial study has led to the development of systemic, hospital-wide electronic medical record order set changes combined with educational interventions which will be evaluated prospectively for its impact on iTTP diagnosis and treatment. Broadly, this study re-demonstrates that the evaluation, diagnosis, coordination, and treatment of iTTP is often logistically challenging. Promoting earlier hematology consultation and optimizing EMR interventions is likely to facilitate appropriate ADAMTS13 testing, expedite results, and help coordinate the initiation of TPE in patients with suspected iTTP. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hemostatic Markers, Adamts-13 Profile and Anti-Sars-Cov-2 Antibody Levels in Patients with Immune Thrombotic Thrombocytopenic Purpura Receiving BNT162b2 Vaccination

▪Introduction: Patients (pts) with immune thrombotic thrombocytopenic purpura (iTTP) are at high risk of severe COVID-19, therefore protection from SARS-CoV-2 by vaccination is particularly relevant in this setting, although concerns may exist on possible adverse reactions or disease relapse after vaccination. In this study, in a group of iTTP pts who received in-hospital COVID-19 vaccination in a special program for ‘fragile patients’, we prospectively evaluated over time the antibody response, the clinical and laboratory disease parameters and hemostatic biomarker levels.Methods: Twelve iTTP pts in clinical remission and regularly followed-up in our Center were enrolled in April 2021, all of them received 2 doses of BNT162b2 vaccine (Pfizer-BioNTech) over 21 days, and were followed-up for clinical and laboratory testing for 60 days. Blood samples were collected at enrollment (day 0, D0) before the 1 st vaccine dose; on day 21 (D21) before the 2 nd dose; and on day 60 (D60) after the 1 st dose. Blood cell counts, anti-Spike receptor-binding-domain protein (anti-S/RBD) IgG, ADAMTS-13 activity, and anti-ADAMTS-13 IgG (chromogenic assay and ELISA), were measured at each time point. Additionally, an extensive study of hemostatic markers (i.e. FVIII, von Willebrand Factor (vWF) antigen and activity, fibrinogen, D-dimer, tPA, PAI, and F1+2) was performed. Follow up is currently continuing.Results: Median age of our cohort was 65 years with M/F ratio of 4/8. Median time since last acute iTTP episode was 40 months, median follow up of the cohort was 71 months (95% CI 30-126). All pts were in clinical remission, except one patient (P1) who had an iTTP relapse after contracting SARS-CoV-2 infection, in Dec 2020, and was on low-dose steroids on D0. One patient (P2) had an ADAMTS-13 relapse in Jan 2021, and received pre-emptive rituximab. No other pts were on immunosuppressive therapy. Concerning the status of ADAMTS-13 activity on D0, 6 pts showed normal levels (>50%), while 5 had a moderate (50-20%) and 1 a complete (<10%) ADAMTS-13 deficiency. This latter patient (P3) had normal ADAMTS-13 activity before the pandemic. All patients were negative for anti-ADAMTS-13 inhibitor. Further, on D0, the anti-S/RBD IgG testing was positive in 3/12 pts (median 704,1 AU/mL), due to symptomatic infection in 1 case (P1), and asymptomatic in 2 (P3 and 1 pt with ADAMTS-13 activity of 54%, P4).The study of hemostatic markers on D0 showed an increase in median levels of FVIII and vWF antigen and activity. These parameters were altered in 7/12, 11/12 and 8/12 pts, respectively. Fibrinogen and D-dimer were increased in 3/12 and 2/12, respectively. Notably, P1, P3 and P4 presented the highest levels of FVIII and vWF antigen, associated with high levels of vWF activity in P1 and P3 (mean 233%); moreover, P3 showed higher levels of D-dimer (708 ng/mL) and tPA (13 ng/ml).After the 2 doses of BNT162b2, no significant clinical side effects were reported, and no changes in platelet counts. ADAMTS-13 activity and inhibitors did not significantly change on D21 and D60. A complete ADAMTS-13 activity deficiency persisted in P3 on D21 and D60, associated with anti-ADAMTS-13 IgG titer >15 U/ml, despite clinical remission. Overall, a significant increase in anti-S/RBD IgG level was observed on D21 (p = 0.0005) and D60 (p = 0.0005). Remarkably, only P2 did not show an increase in anti-S/RBD IgG titer after both doses of BNT162b2. Median levels of FVIII and vWF antigen did not significantly change during follow up, while increased vWF activity was seen on D60 (p = 0.05). Fibrinogen levels were stable, and an increase in D-dimer (>1000 ng/mL both on D21 and D60) was seen in P3. There were no changes in the other hemostatic parameters, and no thromboses were observed.Conclusions: In our cohort of iTTP pts, COVID-19 was associated with 1 clinical and 1 ADAMTS-13 relapse. Our data show that SARS-CoV-2 vaccination was effective in inducing an antibody response in all but one patient who received rituximab within 3 months before vaccination, confirming recent findings. Overall, vaccination had no relevant impact on the hemostatic profile of our pts, and did not appear to be a driver of iTTP relapses. However, anti-SARS-CoV-2 antibodies monitoring in iTTP pts may be useful after vaccination, as currently it is unknown how long the antibody titer may persist. Although small, this study is in favor of efficacy and safety of mRNA vaccines in pts with iTTP. DisclosuresFalanga: Bayer: Honoraria; Sanofi: Honoraria; Leo Pharma: Honoraria; Pfizer: Honoraria.

Efficacy and Safety of Azathioprine during Remission of Immune-Mediated Thrombotic Thrombocytopenic Purpura

▪IntroductionAcquired immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening thrombotic microangiopathy caused by the development of anti-ADAMTS13 autoantibodies. Up to 50% of patients surviving an acute iTTP event experience one or more relapses. Recent guidelines suggest treatment with rituximab in clinical remission in iTTP patients with low ADAMTS13 activity to prevent acute iTTP relapses. A 10% of cases who do not respond to rituximab or develop allergic reactions requiring therapy discontinuation have been reported. In these patients, azathioprine might be an alternative treatment to prevent acute iTTP relapses. The aim of this study was to assess the efficacy and safety of azathioprine treatment in iTTP patients in clinical remission.MethodsWe designed a retrospective cohort study including all iTTP patients treated with azathioprine during clinical remission, enrolled in the Milan TTP Registry between May 2003 and October 2020 and followed for at least six months.The efficacy of azathioprine was assessed in patients with at least four weeks of treatment. The primary outcome was clinical relapse during azathioprine treatment. The secondary outcomes were the partial and complete responses of ADAMTS13 (an ADAMTS13 activity increase above 20% and 45%, respectively) in patients with ADAMTS13 activity below 20% before azathioprine start. ADAMTS13 relapse (an ADAMTS13 activity decrease below 20%) in patients with a prior ADAMTS13 response was also assessed.As for the safety analysis, adverse events (AEs), associated or not with treatment discontinuation, were retrieved from clinical charts of all patients.Lastly, we assessed the association between variables such as sex, age, and concomitant autoimmune diseases, and ADAMTS13 response, using logistic regression models.ResultsWe enrolled 43 patients with iTTP treated with azathioprine during clinical remission (Table 1). Forty-two percent of the patients had at least one concomitant autoimmune disease. The median exposure to azathioprine was 16 months (interquartile range [IQR] 8-49 months), the median dosage 1.3 mg/kg/day (IQR 0.9-1.6 mg/kg/day).Thirty-five cases were available for the primary outcome analysis (Table 2). Seven patients relapsed after a median time of 14 months after azathioprine start (IQR 8-58 months). The cumulative incidence of clinical relapse during azathioprine treatment was 10% at 1 year (95% Confidence Interval [CI] 0-21%), 22% at 2 years (95% CI 6-38%).Twenty-one cases were available for the secondary outcomes analysis. An ADAMTS13 partial response occurred in 10 patients (48%), after a median time of 3 months (IQR 3-9 months) after azathioprine start and lasted for a median time of 40 months (IQR 16-56 months). An ADAMTS13 complete response was achieved in 33% of patients, after a median time of 8 months (IQR 3-16 months) after azathioprine start and lasted for a median time of 16 months (IQR 0-53 months). Of the 10 responders, 3 (30%) had a subsequent ADAMTS13 relapse at 22, 24 and 37 months after azathioprine start.Adverse events were observed in 30% of patients, after a median time of 50 days after azathioprine start (IQR 26-331 days). Liver and pancreas alterations with increased levels of ALT, AST, GGT, ALP and lipase were the most frequent, followed by nausea and leukopenia (Table 3). In one patient, acute myeloid leukemia was diagnosed 6 months after azathioprine start. Fifteen percent of the patients had to stop the treatment due to AEs.No demographic or anamnestic variables were associated with ADAMTS13 response to azathioprine.ConclusionsForty-eight percent of patients attained an ADAMTS13 activity above 20%, with a durable response lasting more than 3 years, while adverse events were generally mild in nature. Azathioprine could be a valid and safe alternative in case of ineligibility or failure to respond to rituximab. [Display omitted] DisclosuresMancini: Instrumentation Laboratory, Sanofi: Honoraria. Peyvandi: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria. OffLabel Disclosure:Azathioprine. It is an immunosuppressive drug used for the prevention of rejection in renal homotransplantation and for treatment of active rheumatoid arthritis.

Incidence of Thrombotic Microangiopathies in Quebec: An 8-Year Overview from a Laboratory Centralizing Adamts-13 Testing

Primary and secondary thrombotic microangiopathies (TMA) constitute a group of life-threatening diseases of different aetiologies characterized by similar symptoms. The comprehensive compilation of data related to TMA is challenging due to their rare occurrence. The objective of this study was to provide an overview of the incidence of thrombotic thrombocytopenia (TTP) and non-TTP TMAs in the Province of Quebec (PQ) (8.485 Million inhabitants in 2019) by taking advantage of the centralized ADAMTS-13 activity and antibody testing for PQ since 2013 at the CHU Sainte-Justine (CHUSJ)All ADAMTS-13 activity and antibody titration were performed locally at CHUSJ. ADAMTS-13 results and patient demographic characteristics from April 2012 to December 2019 were extracted from the Laboratory Information System of CHUSJ and used in an anonymized database. Information on previous TMA episodes was obtained from a standardized clinical assessment form accompanying each plasma sample. Statistical analyses were performed with IBM SPSS version 26.0. The annual incidence rates were calculated based on the number of patients with a first-time recorded diagnosis of TMA using the Quebec mid-year (yr) estimated population of the years at stake. Patients with suspected TMA were further divided into two categories: individuals with TTP, defined by either an ADAMTS-13 activity ≤10% or a positive anti-ADAMTS-13 antibody titration, and patients with a suspected TMA other than TTP (non-TTP TMA) with a result of ADAMTS-13 activity >10%. The study was approved by the Research Ethics Committee of CHUSJ.A progressive increase in the annual requests for ADAMTS13 activity was observed over the study period. The number of new patients increased from 2012 to 2016 but plateaued after 2016 at an average number of 170 new patients per year. The number of confirmed TTP cases in Quebec was higher from 2014 to 2018 compared to in 2012, 2013 and 2019 (Figure 1). A total of 2081 requests for ADAMTS13 activity testing were received during the study period, representing 846 subjects with a suspected TMA. 147 subjects (17%) had a confirmed TTP and 699 (83%) had a suspected non-TTP TMA.TMAs were suspected more often in females (59%), both in confirmed TTP (62%) and non-TTP TMA (58%).The mean annual incidence rate (MAIR) of TTP was 1.91 case/million/yr (95%CI: 1.46-2.35). This was higher in females (2.36 cases/million/yr; 95%CI: 1.34-3.37) compared to males (1.42 case/million/yr; 95%CI: 0.57-1.44; p=0.001). The MAIR of non-TTP TMA was 9.97 cases/million/yr (95%CI:5.85-14.09), 11.52 for females (95%CI:6.71-16.33) versus 8.41 for males (95% CI: 4.81-12.02; p=0.001).In non-TPP TMA, the MAIR for males ranged from 3.9 to 7.2 cases per million prior to 60 year of age and increased after up to 24.5 at ages 80-89. For females, a first peak MAIR above 10 cases per million was observed during their thirties and a second peak was observed during their seventies (Figure 2).In TPP, peaks incidences in females were observed from ages 20 to 49. It dipped from ages 50 to 69 and then increased again. In males, a highest MAIR was observed between ages 40 to 79.In conclusion, the provincial centralization of ADAMTS-13 testing has enabled us to depict comprehensive picture of TTP and other suspected non-TPP TMA, thereby providing valuable information for caregivers and health authorities into these rare diseases. Sex and age related incidences observed in this study are comparable to those obtained through other registries and aggregated studies. Further analyses on clinical presentation of TMAs and patient follow up are now possible using the identification of this large cohort. [Display omitted] DisclosuresLapeyraque: Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rivard: Bayer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma Inc: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk Inc: Membership on an entity's Board of Directors or advisory committees; CSL Behring Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bonnefoy: Sanofi Genzyme Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Initial Clinical Presentation and Predictors of Thrombotic Thrombocytopenic Purpura in Quebec

Thrombotic microangiopathies (TMA) constitute a group of life-threatening diseases of different aetiologies characterized by similar symptoms. The compilation of comprehensive data related to the initial clinical presentation of TMA is challenging due to their rare occurrence.The objective of this study was to assess and determine the predictive value of the clinical presentation of patients with a suspected TMA episode, subsequently confirmed as thrombotic thrombocytopenic purpura (TTP), compared with non-TTP TMA by taking advantage of the centralized ADAMTS-13 testing in Quebec.All ADAMTS-13 activity and antibody titration were performed at CHU Saint-Justine (CHUSJ). Measurements and patient demographics (from April 2012 to December 2019) were extracted from the Laboratory Information System of the CHUSJ. Patients with presumed TMA were classified into TTP when ADAMTS-13 activity was ≤10%, or suspicion of TMA other than TTP (non-TTP TMA) when ADAMTS-13 activity was >10%. Clinical presentation was obtained through a survey form received with each plasma sample and containing information related to prior episodes of TMA, underlying conditions (pregnancy, cancer, infection, transplant, medication, other), clinical symptoms (fever, neurological signs, abdominal signs), and biological parameters (hemolytic anemia, thrombocytopenia). Statistical analyses were performed with IBM SPSS 26.0. The study was approved by the Research Ethics Committee of CHUSJ.A total of 2081 requests for ADAMTS13 testing were received during the study period, in 846 different individuals with suspected TMA: 147 patients (17%) had a confirmed TTP and 699 had a suspected non-TTP TMA. Clinical and biological characteristics associated with TMA suspicion were available for 105 TTP and 470 non-TTP TMA patients (68% of subjects).More than half of patients with TTP (55%; 48/87) had neurological signs at presentation compared to one third of patients (33%; 124/375) with non-TTP TMA (p=0.0001). There were no significant differences regarding fever and abdominal signs between the 2 groups (p=0.383 and p=0.355 respectively). Anemia and thrombocytopenia were reported in 92% (80/87) and 93% (86/92) of TTP patients compared to 74% (291/396) and 83% (352/426) of non-TTP TMA patients (p=0.0002 and p=0.009, respectively). Underlying conditions were reported in 62% (287/460) of non TTP-TMA patients compared to 35% (34/97) of TTP patients (p<0.0001). Kidney involvement was documented in 20% (91/460) of non-TTP TMA and 7% (7/98) of TTP (p=0.003). Transplantation tended to be more often reported in non-TTP TMA (11%;58/560 versus 4%;4/98 in TTP; p=0.079). Pregnancy or postpartum was found in 11% (29/267) of females with non-TTP TMA and 5% (3/57) of females with TTP (p=0.232). Infections were present in 15% (68/462) of non-TTP TMA and 14% (14/98) of TTP (p=0.912). Drug associated TMA was reported in 15% (70/461) of non-TTP TMA and 9 % (9/98) of TTP (p=0.123). Cancers were documented in 16% (74/462) of non-TTP TMA and 9% (9/98) of TTP (p=0.084).When addressing the odds of TPP according to the clinical presentation, patients with neurological signs were at higher risk to be diagnosed with TTP compared to those who did not have neurological signs (odds ratio, 2.52; IC95%, 1.51 to 4.20; p<0.001). Thirty percent of patients presenting with neurological signs had TTP compared to 14% presenting without neurological signs. Conversely, the risk to be diagnosed with TTP was lower in the setting of transplantation (odds ratio, 0.32; IC95%, 0.11 to 0.92; p=0.015). Indeed, among patients who have had a transplantation 7% were diagnosed with TTP, while 93% had non-TTP TMA. Finally, the risk of TPP was also lower in patients with TMA and concomitant kidney-related issue (OR=0.31; IC95%: 0.14 to 0.69; p=0.004) as among patients presenting with renal disorders, 93% were not subsequently diagnosed with TTP.In conclusion, the centralization of ADAMTS-13 activity testing in one reference center has enabled to determine the predictive value of clinical characteristics associated with TPP in comparison to other types of TMA for the entire province of Quebec, Canada. This study provides useful insight for caregivers and paves the way to the establishment of a provincial registry of TMA patients. [Display omitted] DisclosuresLapeyraque: Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rivard: Bayer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma Inc: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Inc: Membership on an entity's Board of Directors or advisory committees. Bonnefoy: Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi Genzyme Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

A Descriptive Analysis of Immune Thrombotic Thrombocytopenic Purpura (iTTP) Patients with Fatal Outcomes in the U.S. Thrombotic Microangiopathy (USTMA) TTP Registry

Background:Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy (TMA) occurring due to an acquired deficiency in ADAMTS13. Mortality due to iTTP is estimated at 10% with current standard treatment that consists of plasma exchange (PLEX) and corticosteroids. The United States TMA (USTMA) registry incorporates 15 large US referral centers across the nation, and includes patients diagnosed with iTTP between 1985 and 2019. We sought to perform a descriptive analysis on the patients with fatal outcomes attributable to acute iTTP episodes in the registry.Methods:We utilized the USTMA registry (n=771) and analyzed twenty-two baseline patient demographics, presenting symptoms, and laboratory findings. The study cohort included participants with iTTP diagnosis based on the presence of thrombocytopenia (platelet count <100 /µL), microangiopathic hemolyic anemia (hemoglobin less than the lower limit of normal with schistocytes on the peripheral blood smear), and either ADAMTS13 activity <10% or ADAMTS13 activity <20% with an anti-ADAMTS13 inhibitor or antibody. For participants diagnosed before the ADAMTS13 assay was developed (2006), the iTTP diagnosis was based on the clinical course and absence of alternative causes. iTTP exacerbation was defined as clinical disease recurrence within 30 days of PLEX discontinuation, and clinical relapse was defined as disease recurrence after 30 days of last PLEX, as per the international working group definitions 1.Results:A total of 33 patients (4.28%) in the USTMA cohort died during acute iTTP episodes. The patient demographics and initial presenting lab values are summarized in Table 1.Time of death (Figure 1):22 patients (66.7%) died during the initial iTTP episode, and within 30 days of presentation.3 patients (9.0%) died during disease exacerbation of the initial episode.8 patients (24.2%) died due to disease relapse.Median time to death at initial presentation/exacerbation (n=25) = 8 days [IQR: 4-19]Median time to death due to relapse = 1.6 years [IQR: 1.1-5.7]Patient demographics and presenting features (Table 1):Median age = 51 years [IQR: 27.8-60]Sex = 54.5% female, 45.5% malePresence of neurologic symptoms on presentation: 22 (66.7%)Presence of any symptoms on presentation: 32 (97%)Conclusion:Patients with fatal outcomes due to acute iTTP episodes presented with variable symptoms and baseline characteristics. While the vast majority of deaths occurred during the initial acute episode, death also occurred during exacerbation of the initial episode or subsequent disease relapse. Vigilant laboratory and clinical monitoring both after achieving initial remission and during long-term follow-up are necessary, to allow detection of disease exacerbation and relapse, and potentially prevent iTTP-related deaths.1. Cuker A, Cataland SR, Coppo P, et al. Redefining outcomes in immune TTP: an international working group consensus report. Blood. 2021;137(14):1855-1861. [Display omitted] DisclosuresMazepa: Answering TTP Foundation: Research Funding; Sanofi Aventis: Other. Lim: Hema Biologics: Honoraria; Sanofi Genzyme: Honoraria; Dova Pharmaceuticals: Honoraria.

Prevalence and Characteristics of Venous Thromboembolism in Patients with Complement Mediated Thrombotic Microangiopathy

BACKGROUND: Microvascular and arterial thromboses are well described in patients with thrombotic microangiopathy (TMA) including complement mediated TMA (CM-TMA)/atypical hemolytic uremic syndrome. Hemolytic disorders are associated with increased risk of venous thromboembolism (VTE), and patients with CM-TMA may have additional risk factors of hospitalization and central lines and may not consistently receive thromboprophylaxis due to thrombocytopenia. However, little is known about the prevalence and clinical correlates of VTE in CM-TMA.METHODS: We performed this single center retrospective cohort study of consecutive patients with CM-TMA enrolled in the Johns Hopkins Complement Associated Disease Registry between January 2014 and December 2020. Data regarding clinical presentation, laboratory studies including clinical complement gene sequencing, terminal complement inhibition and anticoagulation therapy, VTE events including characteristics and risk factors for VTE were collected. A diagnosis of CM-TMA was based on: (1) platelet count <150 × 10 9/L, (2) schistocytes on peripheral blood smear or TMA on renal biopsy, if performed, (3) ADAMTS13 activity >10%, (4) Shiga toxin negative, and (5) serum creatinine >2.25 mg/dL at presentation, which was considered supportive but not required for diagnosis. We only included VTE events post-CM-TMA diagnosis. VTE characteristics, treatment and outcomes were summarized using descriptive statistics. The Chi-squared test and Mann Whitney test were used to compare categorical and continuous variables across groups with and without VTE, respectively.RESULTS: Of 44 patients diagnosed with CM-TMA and followed for a median of 3.1 years (IQR 0.8-5.5), 8 (18.2%) experienced at total of 10 VTE events (5.6 VTE events/100 patient-years). There was no significant difference between patients with and without VTE in age at diagnosis, sex, race, BMI, need for dialysis, treatment with eculizumab, and presence of mutations in complement genes (Table 1).VTE events included 5 deep vein thromboses, 4 pulmonary emboli and 1 splenic infarct (Table 2). The majority (70%) of VTE events were provoked with 5 (50%) associated with a catheter or vascular access for dialysis and 2 (20%) events following major surgeries. The median time from CM-TMA diagnosis to the first VTE event was 4.9 months (IQR 0.76-26) with 3 events occurring during the index hospitalization for CM-TMA. Of 10 VTE events, 5 occurred while on complement inhibition and 2 on anticoagulation (1 on therapeutic and 1 on prophylactic anticoagulation). Of note, only 1 of 3 patients diagnosed with VTE during their index CM-TMA hospitalization received thromboprophylaxis. At the time of VTE diagnosis, the median platelet count was 182.5 x 10 9/L (IQR 143.75-332.75); 80% had a platelet count >150 x 10 9/L , and 10% each had a platelet count <50 x 10 9/L or 50-150 x 10 9/L.VTE was treated with therapeutic anticoagulation with enoxaparin, warfarin or a direct oral anticoagulant in 7 of 8 patients for a median duration of 7 months (IQR 4-14). One patient experienced recurrent PEs; the first PE occurred 2 months following the index CM-TMA hospitalization and the second event was 4 years later while off of anticoagulation and complement inhibition. A second patient experienced a splenic infarct 7 months after initial CM-TMA diagnosis while non-compliant with ravulizumab, followed by a catheter-associated upper extremity DVT 2 months later while on therapeutic anticoagulation and ravulizumab. No VTEs were fatal.CONCLUSION: VTE is common in patients with CM-TMA (18.2%), with a prevalence comparable to thrombotic thrombocytopenic purpura (18%, Tse et al. 2020) but greater than that reported in dialysis patients (Moinar et al. 2017). In CM-TMA patients, VTE is commonly provoked by hospitalization or dialysis catheters and tends to occur after platelet count recovery and in the absence of thromboprophylaxis. Factors such as renal impairment, prolonged hospitalization, complement dysregulation, and free hemoglobin release may also increase VTE risk. Our results highlight the high prevalence of VTE in CM-TMA and the importance of thromboprophylaxis once the platelet count is greater than 50 x 10 9/L. [Display omitted] DisclosuresDane: Alexion: Honoraria; Sanofi Genzyme: Honoraria; Janssen: Honoraria. Chaturvedi: Sanofi Genzyme: Other: Advisory board member; Alexion: Other: Advisory board member; Dova: Other: Advisory board member; Argenx: Other: Advisory board member; UCB: Other: Advisory board participation.

The Efficacy and Safety of Caplacizumab in Japanese Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura (iTTP): An Open-Label, Phase 2/3 Study

The Efficacy and Safety of Caplacizumab in Japanese Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura (iTTP): An Open-Label, Phase 2/3 Study

Caplacizumab Is Effective in Treating Immune-Mediated Thrombotic Thrombocytopenic Purpura in Real-World Scenarios and May Lower Mortality: An Aggregative Analysis

Introduction: The treatment of acquired thrombotic thrombocytopenic purpura has been a subject to change lately due to the introduction of caplacizumab as a novel, and potentially life-saving agent. Here, we compare patient-centered outcomes of a historic cohort of 119 aTTP-patients and an extended real-world caplacizumab-treated cohort of 113 aTTP-patients from Germany and Austria in the context of multiple recently published international cohorts of aTTP patients.Methods: From October 2018 until May 2021, data from German and Austrian patients presenting with an acute episode of aTTP as defined by an ADAMTS13 activity below 10 % treated with caplacizumab were gathered retrospectively. We aggregated data from two published randomized controlled trials (TITAN, HERCULES), one single-arm prospective trial and two retrospective cohorts with a historical control cohort. In total, we report 846 aTTP cases, 396 of those treated with caplacizumab and 450 without. For data analysis, placebo groups from randomized trials and historical controls from retrospective analyses were combined.Results: All cohorts combined reported 30 aTTP-related deaths, predominantly in the non-caplacizumab cohort. Mortality in the caplacizumab-cohort (8 cases total) was mainly driven by 5 reported deaths in the UK-cohort, which have been ascribed to a delayed use of caplacizumab by the authors. The number of daily PEX was significantly less in the caplacizumab-treated cohort (7.2 vs 10.2 days). In line, the number of hospital (14.0 vs 18.1) and ICU (4.7 vs 8.9) days differed significantly. Exacerbations (14% vs 39%) were significantly reduced in the caplacizumab-group. In view of all treatment-related outcomes, the data presented herein argues strongly in favor of an early and consistent use of caplacizumab in all instances of aTTP. DisclosuresVölker: Sanofi-Genzyme: Honoraria, Other: counselling fees.

A Rare Case of Mild COVID-19 Disease Associated with Type 1 Cryoglobulinemia and Thrombotic Thrombocytopenic Purpura

Introduction:Type I cryoglobulinemia (Type I CG) usually develops in the setting of protein-secreting monoclonal gammopathies [1,2]. The estimated frequency of renal involvement is 30% in Type 1 CG. Thrombotic Thrombocytopenic Purpura (TTP) is a life-threatening disease in which there is a deficiency in ADAMTS13, a protease which normally functions to cleave von Willebrand factor (vWF). A deficiency leads to persistence of large vWF multimers and the formation of platelet-rich thrombi in the microvasculature. We present a case of 52 years old female with Type 1 CG and acquired autoimmune TTP secondary to mild Covid-19 disease.Case Report:A 52-year-old woman with medical history significant for CKD stage 2, with baseline creatinine (Cr) of 2.5, Diffuse Large B-Cell Gastric Lymphoma (DLBCL), in complete remission, and recent diagnosis with COVID-19 presented to the ED for evaluation of three days of a petechial rash on her bilateral extremities. Significant labs on arrival included hemoglobin (Hgb) 8.9, platelet count 65, Cr of 3.65, and K+ 6.6, meeting criteria for acute kidney injury (AKI). Peripheral blood smear showedthrombocytopenia and normochromic normocytic anemia with no schistocytes or microangiopathic changes. ADAMTS13 was 43% and there was no clinical suspicion for TTP. The patient's Cr continued to worsen up to 8.1 during admission, prompting renal biopsy. Renal biopsy showed Type 1 cryoglobulinemic glomerulonephritis with vasculitis and 30 to 40% fibrosis of glomeruli. The patient was started on systemic steroids, plasma exchange every 2-3 day (completed 6 sessions) and hemodialysis. Her platelet counts steadily increased to 212 but had a significant drop to 32 when rechecked seven days later, prompting further investigation. ADAMTS13 was rechecked and found to be 5% with presence of inhibitor, Hgb was 7.7, haptoglobin was <20, and a diagnosis of TTP was made. The patient was started on daily plasmapheresis, rituximab, Caplacizumab and high dose systemic steroid therapy. Our patient had prior history of DLBCL and was treated with radiation therapy. Restaging PET/CT and EGD with biopsy showed no evidence of recurrence. Bone marrow biopsy was negative for evidence of lymphoma. Several serologic tests were used to rule out other etiologies of Type I CG and came back negative including: SLE, HIV, hepatitis C, multiple myeloma, and Waldenstrom's macroglobulinemia. The patient had elevations in multiple immune markers including IgG, IgM, free kappa light chains, and free lambda light chains. She also had hypocomplementemia of both C3 and C4.Discussion:The relationship of Type I CG and COVID-19 is unclear, though viral infections can trigger autoimmune diseases [3]. Previously, all patients with Type I CG had either ahematologic malignancy, solid-organ malignancy, infection, or autoimmune syndromes. Interestingly, in our patient, several serologic tests were performed and negative, which ruled out these etiologies of Type I CG. Our patient's manifestation of Type I CG was petechial rash on extremities and acute on chronic renal disease. Specific treatment of CG can include plasma exchange, corticosteroids, rituximab, and hemodialysis, depending on underlying cause. Our patient was started on systemic steroids, plasma exchange every 2-3 days, and hemodialysis due to worsening renal functions. Despite cases of covid-19 and TTP being reported, the relationship between the disease processes remains unclear. COVID-19 infection can cause disproportionate activation of the complement system and lead to excessive coagulation and thrombotic events. Systemic infection can decrease ADAMTS-13 activity, and this has also been noted in COVID studies. ADAMTS-13 deficiency has no pathophysiologic relevance specific to Type 1 CG. Our patient developed anemia and thrombocytopenia, and ADAMTS13 activity testing was found to be 5% with presence of an inhibitor. Considered as high-risk disease, our patient was started on steroids, rituximab, Caplacizumab and daily plasmapheresis. Repeated weekly ADAMTS13 level was 26% and platelets were stabilized at 69k/microL.Conclusion:Suggests that Covid-19 virus has the capability to induce cryoglobulinemia through an unknown mechanism• There are two other case reports of an association between Covid-19 and TTP.• May be the first case indicating a possible association of Covid-19 with cryoglobulinemia. DisclosuresNo relevant conflicts of interest to declare.