RARE DISEASE
Thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Synonyms: Moschcowitz disease, TTP
Synonyms: Moschcowitz disease, TTP
Synonyms: Moschcowitz disease, TTP
Drug discovery
16
drugs
With orphan designations
Overview
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by severe ADAMTS13 deficiency (<10% activity), typically due to autoimmune inhibition (iTTP) or congenital mutations (cTTP). Hallmark features include microangiopathic hemolytic anemia, thrombocytopenia, and ischemic organ damage involving the brain, kidneys, and heart. Without prompt treatment, mortality exceeds 90%, but plasma exchange reduces this to <20%. Diagnosis requires ADAMTS13 activity testing and exclusion of alternative causes of thrombotic microangiopathy. [1][2][9]
Burden
Acute mortality 10-20% with treatment [2][12], but 55-80% of deaths occur within 14 days if undiagnosed [12]. Up to 40% relapse risk over 10 years [4][8]. Long-term complications include hypertension (30-50%), neurocognitive deficits (25-40%), and chronic kidney disease (15-25%) [8][12][13]. Hospitalization costs exceed $100,000 per acute episode with frequent readmissions [12][18].
Therapies
First-line plasma exchange (1.5x plasma volume daily) with corticosteroids (methylprednisolone 1-2 mg/kg/day). Rituximab (375 mg/m² weekly ×4) for refractory/relapsing cases. Emerging therapies include caplacizumab (anti-vWF nanobody) to reduce thrombosis [3][11] and recombinant ADAMTS13 for congenital forms. [3][9]
Categories: rare hematological diseases, rare renal diseases, rare transplant-related disorders
Research Papers
1,785 drug discovery papers about Thrombotic thrombocytopenic purpura, with 4 first-in-class and 15 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,785 drug discovery papers about Thrombotic thrombocytopenic purpura, with 4 first-in-class and 15 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-24 | N-acetylcysteine in Thrombotic Thrombocytopenic Purpura: A Systematic Review.
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy characterized by severe ADAMTS13 deficiency and accumulation of ultralarge von Willebrand factor multimers. Although therapeutic plasma exchange (PEX), corticosteroids, rituximab, and caplacizumab have improved outcomes, refractory and relapsing disease remain important clinical challenges. N-acetylcysteine (NAC) has been explored as an adjunctive therapy because of its ability to reduce disulfide bonds within von Willebrand factor multimers. This systematic review aimed to summarize the published clinical experience with NAC in TTP, including treatment strategies, reported outcomes, and safety. A systematic search of PubMed was performed from database inception until December 31, 2025, using combinations of the terms "thrombotic thrombocytopenic purpura", "TTP", "N-acetylcysteine", and "acetylcysteine". Two reviewers independently screened records, assessed full texts against predefined eligibility criteria, and extracted study-level data. Eligible studies included case reports and case series describing therapeutic NAC use in patients with TTP. The review was conducted in accordance with PRISMA 2020 guidance. The protocol was not prospectively registered. Six publications comprising 22 adult patients were included. NAC was used as adjunctive therapy, predominantly in refractory or relapsing TTP, alongside PEX, corticosteroids, rituximab, and/or other immunosuppressive therapies. Platelet recovery was reported following NAC initiation in the included cases, with concurrent improvement in hemolysis markers and neurologic symptoms described in some reports. No serious NAC-related adverse events were reported in the included cases. Because all evidence was derived from uncontrolled reports with concomitant therapies, the independent contribution of NAC cannot be established. The available case-based literature suggests that NAC is a biologically plausible and generally well-tolerated adjunctive therapy in refractory or relapsing TTP. However, the current evidence remains hypothesis-generating and is insufficient to establish efficacy. Prospective studies are needed to clarify its therapeutic role, optimal dosing, and patient selection.
2026-06-24 | NETs contribute to acute episodes but not ADAMTS13 relapses in immune-mediated thrombotic thrombocytopenic purpura.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) results from acquired severe deficiency of a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13 (ADAMTS13). Neutrophil extracellular traps (NETs) contribute to acute iTTP episodes, but their role across different clinical stages and treatment modalities remains unclear. We conducted a retrospective, observational study in 8 patients with iTTP followed up for 7.4 years (range, 0.4-15.2). Patients experienced 8 first acute episodes (3 caplacizumab treated), 14 ADAMTS13 relapses, and 6 clinical relapses (2 caplacizumab treated), interjected by remissions. Besides clinical and ADAMTS13 parameters, we measured NET markers, including circulating DNA, myeloperoxidase (MPO), neutrophil elastase, and citrullinated histone H3. All NET markers were elevated at presentation with acute iTTP episodes and rapidly declined during treatment. The magnitude of NET marker reduction 3 days after treatment initiation was similar with and without caplacizumab (DNA, -61% ± 21% vs -49% ± 23%; MPO, -15% ± 49% vs -46% ± 33%). In the second week, patients treated without caplacizumab presented with another NET marker surge, paralleled by a drop in platelet counts; both were absent in caplacizumab-treated patients. NET levels remained unchanged during ADAMTS13 relapses compared to remission (DNA, 1.1-fold; MPO, 1.1-fold), whereas increases were documented in overt clinical relapses (DNA, 4.3-fold; MPO, 3.2-fold). Our findings indicate NET involvement in acute iTTP pathophysiology but suggest that NET formation requires a secondary trigger beyond ADAMTS13 deficiency. The second wave of NET formation and renewed platelet decline may be driven by von Willebrand factor-platelet interactions, as the phenomenon is absent in caplacizumab-treated patients. Our data support the benefit of preemptive immunosuppressive treatment for ADAMTS13 relapses.
2026-06-10 | Autophagy, NET formation, and inflammation crosstalk in thrombotic autoimmune diseases.
Neutrophil extracellular traps (NETs), released by activated neutrophils, are essential components of innate immunity, capturing and neutralizing pathogens. Dysregulated NET formation can both initiate and perpetuate inflammation, autoimmunity, and thrombosis. When NETs are excessively produced or insufficiently cleared, they expose autoantigens, fuel cytokine and interferon responses, and induce endothelial damage. In addition, NETs promote platelet adhesion, activate coagulation, and impair fibrinolysis, thereby establishing them as central drivers of immune-mediated thrombotic pathology. This review focuses on three representative thrombotic autoimmune diseases, namely immune thrombocytopenia (ITP), heparin-induced thrombocytopenia (HIT), and immune-mediated thrombotic thrombocytopenic purpura (iTTP), in which pathogenic autoantibodies and persistent NETs contribute to both thrombocytopenia and thrombosis. In ITP, endothelial activation and excessive NET release are associated with increased thrombotic risk. In HIT, platelet factor 4 (PF4)-NET complexes enhance thrombus formation while showing resistance to DNase-mediated degradation. Lastly, in iTTP, elevated levels of NET components correlate with platelet consumption and disease severity. Autophagy emerges as a central regulatory mechanism that shapes NET formation and immune activation. While autophagy supports pathogen clearance and maintains immune homeostasis, its dysregulation can amplify NET formation, sustain chronic inflammation, and promote loss of tolerance. This review proposes an interconnected model in which autophagy, NETs, and inflammation mutually reinforce one another, thereby driving thrombotic autoimmune diseases. Furthermore, it explores pharmacological agents targeting autophagy as potential treatment approaches aimed at disrupting the autophagy-NET-inflammation crosstalk and restoring immune homeostasis.
2026-05-11 | Clinical presentation and treatment outcomes in a South African thrombotic thrombocytopenic purpura cohort with and without HIV.
HIV is the most common cause of secondary thrombotic thrombocytopenic purpura (TTP) in South Africa. To assess the clinical presentations and outcomes of patients treated for HIV-associated and idiopathic TTP. We conducted a retrospective cohort study of patients consecutively diagnosed with TTP from 2010 to 2020 at Groote Schuur Hospital. Patients were identified by reviewing hospital and Western Cape Blood Services records. Kaplan-Meier curves and log-rank tests were used to evaluate remission rates, both overall and by HIV status and treatment group. Logistic regression models were used to identify predictors of remission and relapse. One hundred and thirty-nine patients were included, 85.6% of whom were HIV positive. There were no significant differences in the TTP pentad features by HIV status. Most patients achieved remission (71.9%) with a median time of eight days. Remission occurred significantly earlier in those treated with fresh frozen plasma only, suggesting less severe disease (median = 8 days [interquartile range 6-10]), compared to those requiring plasma exchange, suggesting more severe disease (median = 12 days [interquartile range 8-22]). The overall mortality in the 10-year period was 38.9%, with 10.8% of the surviving patients relapsing after 6 months. There were no significant differences in remission status, time to remission, mortality or relapse by HIV status. All HIV-positive patients who relapsed had defaulted their antiretroviral therapy (ART). HIV status did not affect patient outcomes in our cohort. ART is important in preventing HIV-associated TTP and relapse.
2026-04-14 | N-Acetylcysteine Therapy in Thrombotic Thrombocytopenic Purpura: A Systematic Review and Critical Appraisal.
Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition resulting from a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, leading to the accumulation of ultra-large von Willebrand factor (vWF) multimers and widespread microvascular thrombosis. While therapeutic plasma exchange and immunosuppression have significantly improved response, refractory and relapsed disease are significant challenges. N-acetylcysteine (NAC) has emerged as a biologically plausible adjunctive therapy due to its potential to reduce disulfide bonds in vWF multimers. However, its clinical role is unclear. This systematic review aimed to evaluate the clinical evidence regarding the efficacy and safety of N-acetylcysteine in patients with immune-mediated TTP. Methods: We performed a systematic review in accordance with the PRISMA guidelines. PubMed/MEDLINE, Google Scholar, and ClinicalTrials.gov were searched until January 2026. Studies involving patients with immune-mediated TTP treated with NAC were included. Case reports, case series, and observational studies involving patients with immune-mediated TTP treated with NAC were included. Risk of bias was evaluated using adapted quality assessment tools. Results: Sixteen studies encompassing 69 patients met the inclusion criteria. Most reports were case reports or small case series; two were larger observational cohorts. NAC was predominantly used as adjunctive therapy in relapsed or refractory TTP. Dose regimens varied. Platelet recovery following NAC was reported within 1-15 days in responding cases. Predominantly positive haematological responses were observed in small series. Significant heterogeneity in patient populations, timing of initiation, concomitant therapies, and outcome reporting limited causal inference. Conclusions: The current evidence suggests that NAC has a biologically rational and potentially adjunctive value in TTP, particularly in refractory disease or resource-constrained settings. However, current data are largely heterogeneous and derived from low-level evidence. Well-designed prospective studies and randomized controlled trials are needed to determine whether NAC provides significant clinical benefit beyond standard therapy.
cell therapies
2026-08-06 | Reversal of refractory systemic lupus erythematosus-associated immune thrombotic thrombocytopenic purpura and cerebritis via optimized lymphoplasmapheresis: a case report and literature review.
Systemic lupus erythematosus (SLE) complicated by immune thrombotic thrombocytopenic purpura (iTTP) and lupus cerebritis is a severe clinical event. Standard therapeutic plasma exchange (TPE) frequently fails in this context due to a "rebound effect", as it clears circulating antibodies but spares the intravascular reservoir of autoreactive lymphocytes. A 30-year-old male presented with refractory SLE, severe iTTP (platelet count: 5.00 × 10^9/L; ADAMTS13 activity: 1.49%), and imaging-confirmed lupus cerebritis. The patient underwent a unique "A-B-A" treatment trajectory. While five sessions of standard TPE at an outside facility did not fully halt the hyper-regenerative hemolysis and CNS progression, the implementation of an optimized lymphoplasmapheresis (LPE) regimen at our center induced rapid hematological remission, progressive radiological resolution of brain lesions, and the alleviation of immune-mediated renal injury, culminating in restored renal function and decreased proteinuria. The optimized LPE protocol utilized a novel dual-parameter modulation (synchronizing blood drawing speed and hematocrit) to precisely extract the pathogenic lymphocyte-rich buffy coat without exacerbating anemia. Paired quantitative analysis of the patient's peripheral blood and LPE effluent provided direct evidence of substantial cytokine (e.g., IL-10, IL-8, TNF-α) clearance. This facilitated the rapid seroconversion of antinuclear and anti-dsDNA antibodies. Furthermore, this targeted cellular depletion reduced the required allogeneic replacement plasma volume by up to 50% compared with standard TPE, conserving blood bank resources. Optimized LPE may interrupt the autoimmune cascade by simultaneously reducing circulating humoral mediators and lymphocyte-rich cellular components. This single-case observation supports its potential as a resource-sparing rescue strategy for refractory autoimmune microangiopathy, although further validation is required.
2026-07-27 | Platelet Transfusion in Patients With Low ADAMTS13-Confirmed Thrombotic Thrombocytopenic Purpura Is Associated With Increased Mortality.
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by severe ADAMTS13 deficiency. Platelet transfusions are generally contraindicated but are often administered before TTP is recognized. To evaluate the association between platelet transfusion in the emergency department (ED) and outcomes in laboratory-confirmed TTP. We conducted a retrospective multicenter cohort study using the TriNetX Research Network (2014-2025). Adults presenting to the ED with ADAMTS13 activity < 10% who received plasma exchange within 48 h were included. The exposure was platelet transfusion within 24 h. The primary outcome was 30-day all-cause mortality; secondary outcomes included myocardial infarction (MI), stroke, intracranial hemorrhage, thrombosis, and ICU-level care. Propensity score matching (1:1) and Cox modeling were performed. Among 693 patients, 99 (13.9%) received platelet transfusion. After matching, platelet transfusion was associated with higher 30-day mortality (30.0% vs. 13.3%; OR 2.79, 95% CI 1.31-5.93; p = 0.008) and increased MI. In Cox analysis, platelet transfusion remained independently associated with mortality (adjusted HR 2.45, 95% CI 1.24-4.85). In confirmed TTP, early platelet transfusion was independently associated with increased short-term mortality, supporting recommendations to avoid platelet transfusion and emphasizing early recognition.
2026-07-26 | Real-time, Multidisciplinary Approach of Women With Pregnancy-Associated Thrombotic Microangiopathy.
Thrombotic microangiopathies (TMAs) occurring during pregnancy or the immediate postpartum period are a rare, and highly complex syndrome. Determination of the most appropriate therapeutic strategy remains challenging and requires individualized assessment. To support both diagnostic and therapeutic decision-making, a national multidisciplinary consultation committee [MCC] (titled "TMA and Pregnancy") was established in October 2023 under the auspices of the French National Reference Center for TMAs. The MCC is activated for a single case, on an emergency basis, and within 24 hours. It brings together national experts from 8 medical specialties. Here, we report on 2 years of experience of the MCC, including operational aspects, activity indicators, the clinical and obstetrical profiles of the first 76 women whose cases were reviewed, the suspected diagnoses, and the real-time impact on patient management. Of the women, 29 (38%) were primiparous. The obstetrical context was preeclampsia in 47% and peripartum hemorrhage (PPH) in 40% of the women. TMA was most frequently attributed to severe endotheliosis, with acute kidney injury (AKI) present in 47 women (62%), including 9 (12%) showing renal cortical necrosis (RCN). Thrombotic thrombocytopenic purpura (TTP) was relatively uncommon (n = 13, 17%), and no cases were considered to represent atypical hemolytic and uremic syndrome (aHUS). The MCC led to a change in management in 26% of cases, most often a deescalation of therapy. We emphasize the value of real-time multidisciplinary case conferences in managing catastrophic obstetrical syndromes and advocate for the recognition of extreme phenotypes of endotheliosis extending beyond the liver. These findings underscore the need for therapies targeting endothelial injury.
2026-07-01 | Redefining Limits: Extracorporeal Cardiopulmonary Resuscitation in Adult Thrombotic Thrombocytopenic Purpura.
Thrombotic thrombocytopenic purpura (TTP) is a rare hematologic emergency that can rapidly progress to multiorgan failure and death if untreated. The role of extracorporeal membrane oxygenation (ECMO) in this setting is limited, and extracorporeal cardiopulmonary resuscitation (ECPR) has not been previously described. We report a case of a pregnant woman with suspected TTP who developed refractory pulseless electrical activity cardiac arrest before initiation of plasma exchange. Extracorporeal cardiopulmonary resuscitation with venoarterial ECMO was initiated despite profound thrombocytopenia (platelets 8,000/μL) as a bridge to definitive therapy, with rapid recovery of cardiac and renal function. She achieved full neurologic recovery and was discharged home without functional deficits. This case highlights the potential role of ECPR as a life-saving bridge in selected patients with TTP despite severe thrombocytopenia.
2026-04-16 | Establishing reverse chimeric antigen receptor T cells for precise targeting of immunemediated thrombotic thrombocytopenic purpura.
Immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP) is a life-threatening autoimmune disorder caused by autoantibodies that target the metalloprotease ADAMTS13. This prevents the cleavage of Ultra-Large von Willebrand Factor (UL-VWF), thereby forming microthrombi in the microvasculature. While current treatments are effective, ADAMTS13 relapses occur in up to 15% of the patients after rituximab administration. In this study, we propose a novel approach addressing the unmet need for treatment of patients with ADAMTS13 refractoriness and for patients requiring repeated treatment. Our strategy involves developing two targeted therapies that aim to achieve highly effective and safe B cell depletion. For the first time, we employ adapter Chimeric Antigen Receptor (CAR) T cells called Reverse CAR (RevCAR) T cells to (i) achieve a broader and deeper B cell depletion by targeting CD19 and (ii) selectively deplete the disease-causing anti-ADAMTS13 autoreactive B cells to increase precision and safety in iTTP treatment. Therefore, we have developed novel Target Modules (RevTMs) against CD19+ and anti-ADAMTS13 autoreactive B cells. We show that the RevCAR T cells successfully and specifically kill target hybridomas and Nalm-6 cells in a RevTM-dependent manner and at low effector-to-target cell ratios. Moreover, the RevCAR T cells are able to eliminate the target cells even in the presence of high concentrations of ADAMTS13 autoantibodies. Overall, our findings demonstrate for the first time, a proof-ofconcept that anti-ADAMTS13 autoreactive B cells can be selectively depleted by the RevCAR T cell platform paving the way for an effective and safe therapy for iTTP.
proteins
2026-09-07 | ADAMTS-13 fusion constructs with dual activity against von Willebrand factor: a novel strategy for immune-mediated thrombotic thrombocytopenic purpura.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy. iTTP pathophysiology stems from severe a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS-13) deficiency caused by autoantibodies, leading to accumulation of ultralarge von Willebrand factor (VWF) multimers and microvascular thrombosis. Engineered ADAMTS-13 variants reduce autoantibody binding. However, some show impaired VWF-cleaving activity, whereas others, such as glycan-engineered variants, retain proteolytic function. To investigate the AU/VWFa-11 (aVWF) single-domain antibody (sdAb) targeting the A1 domain of VWF in its active conformation, and 2 dual-action fusion constructs linking the sdAb to either a truncated ADAMTS-13 (Metalloprotease, Disintegrin, Thrombospondin type 1 repeat, Cysteine-rich and Spacer domains [MDTCS]; MDTCS-aVWF) or an autoantibody-resistant mutant (MDTCSm; MDTCSm-aVWF). Binding of aVWF to active VWF and the VWF A1 domain was assessed by enzyme-linked immunosorbent assays. Proteolytic activity was assessed using fluorescence resonance energy transfer substrate (FRETS)-VWF73, VWF multimer, and beads-on-a-string assays. VWF-platelet interactions were measured by light transmission aggregometry and flow cytometry. Autoantibody resistance was evaluated using FRETS-VWF73 assays in the presence of plasma from iTTP patients. aVWF sdAb selectively bound active VWF and inhibited platelet-VWF interactions in solution without impairing platelet adhesion to collagen-bound VWF. Both MDTCS-aVWF and MDTCSm-aVWF retained high proteolytic activity against VWF and reduced platelet-VWF interactions. Notably, MDTCSm-aVWF showed enhanced proteolytic activity and greater resistance to iTTP autoantibodies. The fusion construct MDTCSm-aVWF, which combines an enzymatically active, autoantibody-resistant ADAMTS-13 variant with a VWF conformation-specific inhibitory sdAb, offers a novel alternative therapeutic approach for iTTP.
2026-07-29 | Case Report: Albumin combined with plasma exchange in the treatment of refractory thrombotic thrombocytopenic purpura.
This study aims to analyze the clinical characteristics and causes of misdiagnosis in patients with thrombotic thrombocytopenic purpura (TTP) presenting with initial neurological symptoms, so as to provide reference for reducing misdiagnosis; to explore the feasibility and efficacy of albumin combined with plasma exchange in the treatment of TTP patients when plasma inventory is insufficient; and to put forward key precautions for TTP diagnosis and treatment, so as to provide strategic support for the treatment of similar cases. Clinical data of the patient (medical history, examination results, diagnosis and treatment records, etc.) were collected retrospectively; albumin combined with plasma exchange was adopted when plasma inventory was insufficient; laboratory indicators and symptom recovery were dynamically monitored to evaluate the effectiveness and safety of the treatment; misdiagnosis risks and the current status of alternative treatment were analyzed combined with literature review. Thrombotic thrombocytopenic purpura with initial neurological symptoms is easily confused with cerebral infarction, and thrombocytopenia of unknown origin is a key clue for differential screening. TTP should be excluded before platelet transfusion; when plasma inventory is insufficient, albumin combined with plasma exchange is feasible and effective for the treatment of AB-blood-type TTP, which can provide an alternative strategy for clinical practice; early diagnosis, timely targeted treatment and multidisciplinary collaboration are the keys to improving the prognosis of TTP patients.
2026-02-16 | Genetics of thrombotic thrombocytopenic purpura: systematic review in immune and congenital thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by severe deficiency of the metalloprotease ADAMTS13. TTP has 2 subtypes: immune (iTTP) and congenital (cTTP). Autoimmune mechanisms underlie iTTP; however, the genetic factors influencing disease risk, relapse risk, and response to treatment are incompletely understood. In cTTP, although variants are described throughout the ADAMTS13 gene, the effect of many of these variants is uncertain. We conducted a comprehensive literature review of both iTTP and cTTP, incorporating findings from genome-wide association studies, case-control studies, registry publications, and population-level databases. In iTTP, 9 studies have investigated the effect of HLA alleles, with HLA-DRB1∗11 most consistently associated with an increased risk, and HLA-DRB1∗04 with protection. However, effect sizes varied across ancestral populations, as we highlight in a meta-analysis of available studies. Beyond the HLA locus, a genome-wide association study in iTTP patients with European ancestry identified a locus on chromosome 3 (rs9884090) associated with a reduced iTTP risk. In cTTP, we identified 364 variants within the literature, the majority (199, 54.7%) being missense variants within coding regions. Although variants are located across the gene, the highest density of variants was observed within exon 7 (32 variants, 8.8% of the total), corresponding to the metalloprotease domain. Finally, analysis of population-level constraint data from gnomAD offered additional insight into the tolerance of ADAMTS13 to variation. Together, these findings highlight the complexity of the genetic factors influencing TTP, and the value of combining clinical information and population data to increase understanding of the disease.
2026-01-31 | Pathogen-reduced plasma, cryoprecipitate reduced for therapeutic plasma exchange.
Therapeutic plasma exchange (TPE) for thrombotic thrombocytopenic purpura (TTP) and auto-immune disorders involves repeated patient exposure to allogenic plasma with the risk of transfusion-transmitted infection (TTI). Amotosalen-UVA Pathogen Reduction technology is FDA approved to manufacture pathogen-reduced plasma, cryoprecipitate reduced (PRPCR), a form of cryoprecipitate poor plasma (CPP) with potentially improved TPE outcomes and reduced TTI risk. PRPCR was manufactured from pathogen-reduced (PR) plasma. Thrombin generation, fibrinogen, Factors II, V, VII, VIII, IX, X, XI, XIII, VWF, ADAMTS13, Protein C, Protein S, α-2 plasmin inhibitor (α-2 PI), IgG, IgM, and IgA were measured. Microfluidic chamber assays at variable shear rates characterized PRPCR-mediated platelet adhesion and aggregation. Compared to PR plasma, fibrinogen, Factor VIII, and VWF levels were depleted in PRPCR. Factors II, V, VII, IX, X, XI, XIII, thrombin generation, Protein C, Protein S, α-2 PI, ADAMTS13, and immunoglobulins were conserved. At low wall shear rates (300 s-1) PRPCR supported platelet adhesion. Perfusion of plasma-free blood containing PRPCR flowed over immobilized VWF binding peptide (100 μg/mL) and showed absence of platelet adhesion. Perfusion of plasma-free blood containing PRPCR flowed over immobilized collagen (200 μg/mL) at high wall shear rate (1500 s-1) and demonstrated no platelet thrombus formation. PRPCR retained hemostatic capacity, anti-thrombotic proteins, and ADAMTS13, but collagen induced platelet aggregation was negligible at high shear due to depletion of functional high molecular weight VWF. PRPCR is a CPP option for TPE with reduced platelet-mediated thrombotic risk and TTI risk, but with retention of plasma hemostatic capacity and immunoglobulins.
2025-12-14 | Thrombotic thrombocytopenic purpura following allogeneic hematopoietic stem cell transplantation: a rare but fatal complication.
Thrombotic microangiopathy (TMA) is a common and potentially fatal complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Thrombotic thrombocytopenic purpura (TTP), a distinct form of TMA caused by severe deficiency of plasma ADAMTS-13 activity, has been reported to be rare in the posttransplant population. To investigate the clinical features and outcomes of TTP after allo-HSCT. This retrospective cohort study used a nested case‒control approach. For each patient with TTP, 3 patients with high-risk transplant-associated TMA (TA-TMA) were matched as controls according to the time of transplantation. A total of 26 patients with TTP were identified and included in the cohort. Compared with patients with high-risk TA-TMA, patients with TTP had greater proportions of central nervous system (50.0% vs 19.2%, P = .002) and gastrointestinal tract involvement (65.4% vs 32.1%, P = .003), with central nervous system dysfunction occurring later (8.0 days vs -1.0 days since the diagnosis of TTP, P = .008). Patients with TTP had a significantly lower overall survival rate than those with high-risk TA-TMA (26.9% vs 48.7%, log-rank P = .026). Age >40 years at the time of TTP diagnosis was identified as an independent predictor of 60-day overall survival. TTP occurring in the setting of HSCT is rare but can be differentiated from TA-TMA and is associated with a worse prognosis.
antibodies
2026-09-23 | Cerebral Small Vessel Disease in Immune-Mediated Thrombotic Thrombocytopenic Purpura Patients During the Acute Phase and Disease Remission.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy characterized by acute neurological manifestations and long-term sequelae related to microvascular brain injury. Cerebral small vessel disease (cSVD), detectable on MRI through lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces, is a risk factor for stroke and cognitive decline, but its prevalence and evolution in iTTP are unknown. We conducted a prospective study of consecutive patients with acute iTTP and age-matched controls to assess the prevalence and one-year progression of cSVD. Brain MRI was performed at enrollment and repeated after 12-18 months in clinical remission. cSVD burden was quantified using a standardized 0-4 score based on four MRI markers. Twenty-five patients (median age 56 years; 60% women) were enrolled. Acute focal ischemic lesions were detected in 13 (52%). cSVD was present in 48% of patients versus 27% of controls, while moderate burden (score ≥ 2) occurred in 24% versus none. Ordinal logistic regression showed an association between iTTP and higher cSVD scores (OR 3.19, 95% CI 1.00-10.14), independent of traditional cardiovascular risk factors. Follow-up MRI was available in 22 patients (88%). In paired analyses, cSVD prevalence increased from 50% to 64%, moderate-to-high burden from 27% to 41%, and six patients (27%) showed score progression. At 1 year, patients had higher odds of greater cSVD burden than controls (age- and sex-adjusted ordinal OR 7.00, 95% CI 1.65-29.74). These findings indicate that cSVD is common during acute iTTP and progresses during the first year despite hematological remission.
2026-09-15 | Unintended Interruption of Caplacizumab Therapy Can Compromise Outcomes in Immune-Mediated Thrombotic Thrombocytopenic Purpura: Lessons from Two Clinical Cases.
Background: Caplacizumab is a cornerstone in the management of immune-mediated thrombotic thrombocytopenic purpura (iTTP), in combination with plasma exchange (PEX) and immunosuppression. Pivotal trials and real-world data have demonstrated faster platelet count recovery and improved remission rates. Nevertheless, a subset of patients still experiences exacerbations or delayed response. Observational evidence suggests that unintended treatment interruptions may contribute to these unfavorable outcomes. Methods: We report on two patients with iTTP treated with caplacizumab and immunosuppression; PEX was used in Case 1 and as escalation therapy in Case 2. Laboratory parameters including platelet count, lactate dehydrogenase (LDH), ADAMTS13 activity, and anti-ADAMTS13 autoantibodies were monitored. Results: In the first case, a 29-year-old female experienced an exacerbation and ischemic complications after two individual caplacizumab doses were unintentionally missed on days 12 and 14. Subsequent continuous administration led to stabilization and recovery. In the second case, a 42-year-old male presented with hemolytic anemia, thrombocytopenia, and ADAMTS13 activity of 1% and was initially treated with prednisolone and caplacizumab without PEX. Two individual caplacizumab doses were unintentionally missed on days 3 and 5 and were followed by delayed treatment response and microembolic infarcts. Treatment escalation to PEX and rituximab and reinitiation of continuous caplacizumab administration led to clinical stabilization. Conclusions: Even brief interruptions of caplacizumab therapy may compromise outcomes in iTTP. Continuous administration and secured availability, together with serial monitoring of ADAMTS13 activity to guide treatment duration and discontinuation, are essential to improve patient care.
2026-09-13 | Case report: Caplacizumab without plasma exchange for severe thrombotic thrombocytopenic purpura.
A 45-year-old female Jehovah's Witness presented with transient expressive aphasia, blurred vision, and dizziness for several hours. A complete blood count (CBC) showed anemia (hemoglobin: 6.3 g/dL), thrombocytopenia (platelet count: 21 × 103/µL), and undetectable haptoglobin. The peripheral smear revealed schistocytes, confirming microangiopathic hemolytic anemia; immune-mediated thrombotic thrombocytopenic purpura (iTTP) was confirmed with an ADAMTS13 level of less than 5% and a positive ADAMTS13 inhibitor screen. Treatment with high-dose corticosteroids was urgently initiated, but the patient and her husband declined plasma exchange based on their beliefs as Jehovah's Witnesses. The patient acutely decompensated, requiring intubation, with worsening of laboratory values (hemoglobin: 3.8 g/dL; platelet count: 9 × 103/µL), elevated serum troponin, and renal and hepatic compromise. In addition to rituximab and intravenous immune globulin, caplacizumab therapy was undertaken. The patient's condition improved clinically, but from a laboratory value perspective, 1 month after caplacizumab initiation, her ADAMTS13 level remained less than 5%. Further immunosuppression with intravenous cyclophosphamide was initiated, which resulted in complete normalization of ADAMTS13 activity. This is the first report of caplacizumab use in a Jehovah's Witness patient with TTP with severe neurological compromise to the point of necessitating intubation and with this degree of anemia. With the eventual addition of cyclophosphamide therapy, we observed complete recovery of this critically ill patient without the use of plasma exchange in the treatment course.
2026-09-08 | Evidence for the use of anti-CD20 therapeutic antibodies in immune thrombotic thrombocytopenic purpura management: a review.
Immune thrombotic thrombocytopenic purpura (iTTP) is an autoimmune thrombotic microangiopathy caused by antibody-mediated deficiency of the plasma metalloprotease ADAMTS13. Therapeutic antibodies that target antibody-producing B-cells via the CD20 surface receptor protein to prevent disease exacerbation and relapse have become part of the standard of care of patients with iTTP. However, clinical trial data regarding the use of anti-CD20 agents is limited to mostly phase II studies; no universally agreed-upon standardized protocol for the use of CD20-targeting antibodies for iTTP regarding choice of agent, dosage, or duration of treatment exists; refractoriness or lack of response to anti-CD20 antibodies can occur; and several agents and biosimilars are now available for the treatment of iTTP patients, which complicates the decision tree for clinicians caring for these patients. In this review, we explore the current landscape of anti-CD20 therapeutics used to treat iTTP, focusing on agents currently available for clinical use. We describe the pharmacokinetic and pharmacodynamic properties of CD20-targeting antibodies; available data regarding dosage and duration of treatment; anti-CD20 antibody therapy refractoriness or lack of response; and the evolving role of anti-CD20 biosimilars. This review will shed light on the state-of-the-art in CD20-targeting antibodies used to treat iTTP patients with an eye toward identifying areas in need of further study to aid in the care of patients with this rare and often devastating disease.
2026-09-01 | Refractory Acquired Thrombotic Thrombocytopenic Purpura in the Third Trimester of Twin Pregnancy: A Case Report
Background: Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening condition triggered by pregnancy, often in the third trimester, and frequently mimics preeclampsia or HELLP syndrome due to shared features like thrombocytopenia. Refractory cases in twin pregnancies, described in this case, pose unique diagnostic and therapeutic challenges, requiring advanced interventions. Case Presentation: A 29-year-old woman carrying dichorionic-diamniotic twins presented in the third trimester with palpitations, dyspnea, oral bleeding, numbness, chest heaviness, fatigue, edema, and pelvic pain. Admission showed severe thrombocytopenia (8 × 10 9 /L), microangiopathic hemolytic anemia (schistocytes, elevated LDH), normal blood pressure, and normal liver/kidney function, making preeclampsia/HELLP unlikely. Because of the high bleeding risk posed by the profound thrombocytopenia, and despite a reassuring fetal assessment, an emergency cesarean section was performed and delivered two healthy baby girls with good Apgar scores. ADAMTS13 activity < 10% subsequently confirmed acquired TTP. Plasma exchange and corticosteroids were started presumptively on the day of admission; because the platelet response was incomplete, rituximab and caplacizumab were added during the same admission. The patient was discharged after initial hematologic recovery but relapsed with recurrent severe thrombocytopenia three days later, confirming refractory disease; she was readmitted and achieved sustained platelet normalization with continued plasma exchange, rituximab, and caplacizumab. Complications included wound infection with multiple organisms, antibiotic allergy, and superficial venous thrombosis, all managed successfully. Both mother and infants were discharged well, with no further relapse at six-week follow-up. Future pregnancies were discouraged without specialist review. Conclusions: High suspicion for TTP is essential in pregnant patients with thrombocytopenia and hemolysis, even without hypertension. Rapid ADAMTS13 testing, timely delivery, and combined plasma exchange with rituximab and caplacizumab enabled full recovery in this refractory twin-pregnancy case. Multidisciplinary care is critical to differentiate from obstetric mimics and achieve favorable outcomes. Keywords: TTP, twin pregnancy, ADAMTS13, caplacizumab, case report
other
2026-09-14 | Immune Thrombotic Thrombocytopenic Purpura Presenting as an Acute Stroke Mimic in a Young Pakistani Man.
Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy that can have acute neurological symptoms and resemble ischemic stroke. A 27-year-old Pakistani man was transported by ambulance after being found unconscious, unable to speak, and unable to move his right side, which was suspected to be a stroke. He had been unwell for two weeks, was clinically jaundiced, and had a possible seizure during the previous week. Urgent plain computed tomography (CT) and CT angiography of the brain were called and revealed no acute abnormality and no obvious large vessel occlusion. There was no evidence of acute infarction on magnetic resonance imaging. His National Institutes of Health Stroke Scale (NIHSS) score was 15/42, which is a moderate stroke. Laboratory studies showed hemoglobin 6.0 g/dL, platelet count 3x109/L, schistocytes on peripheral smear, lactate dehydrogenase 2139 U/L, haptoglobin <0.01 g/L, reticulocytosis, and mainly indirect hyperbilirubinemia. The clinical features were compatible with iTTP complicated with neurological involvement. The patient was treated with therapeutic plasma exchange daily, high-dose methylprednisolone, and rituximab. Platelets rose steadily to 199x109/L on day 8, bilirubin levels dropped to 14.2 µmol/L, and lactate dehydrogenase levels dropped to 259 U/L at discharge. Neurological recovery was quick, with resolution of the right-sided weakness by the fourth hospital day and an NIHSS score of 0. This case highlights that in young patients with stroke-like presentation, severe thrombocytopenia, and microangiopathic hemolytic anemia, prompt plasma exchange and immunosuppression can be lifesaving and should be considered in iTTP.
2026-07-09 | Update in treatment options for congenital and immune thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy resulting either from congenital deficiency (cTTP) or acquired (immune) deficiency (iTTP) of A Disintegrin and Metalloprotease with ThromboSpondin-type 1 motif, member 13 (ADAMTS13). Deficiency of ADAMTS13 leads to disseminated platelet thrombosis and organ dysfunction. High mortality of cTTP is prevented by plasma infusion to replace the deficient protease, or more recently by infusion of recombinant ADAMTS13. Standard treatment of iTTP includes steroids, plasma exchange, and rituximab, with or without caplacizumab. Although standard treatment of iTTP improves mortality, refractory cases persist, indicating the need for additional treatment options. This review summarizes the status of novel treatment options for cTTP and iTTP, including additional recombinant ADAMTS13 products, ADAMTS13 gene therapies, plasma cell-directed therapies (bortezomib, daratumumab) as well as novel inhibitors of von Willebrand factor activity.
2024-09-12 | Emerging Thrombotic Disorders Associated with Virus-Based Innovative Therapies: From VITT to AAV Gene Therapy-Related Thrombotic Microangiopathy.
Gene therapy is a promising therapeutic approach for treating life-threatening disorders. Despite the clinical improvements observed with gene therapy, immune responses either innate or adaptive against the vector used for gene delivery, can affect treatment efficacy and lead to adverse reactions. Thrombotic microangiopathy (TMA) is a thrombosis with thrombocytopenia syndrome (TTS) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and small vessel occlusion known to be elicited by several drugs, that has been recently reported as an adverse event of adeno-associated virus (AAV)-based gene therapy. TMA encompasses a heterogenous group of disorders, its classification and underlining mechanisms are still uncertain, and still lacks validated biomarkers. The identification of predictors of TMA, such as vector dose and patient characteristics, is a pressing need to recognize patients at risk before and after AAV-based gene therapy administration. This review aims to explore the literature on TMA associated with AAV-based gene therapy in the larger context of TMA (i.e., hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, and other drug-related TMAs). Considering the wide attention recently gained by another TTS associated with a non-gene therapy viral platform (adenovirus, AV COVID-19 vaccine), namely vaccine-induced immune thrombocytopenia and thrombosis (VITT), AAV gene therapy-related TMA mechanisms will be discussed and differentiated from those of VITT to avoid recency bias and favor a correct positioning of these two recently emerged syndromes within the heterogenous group of drug-related TTS. Finally, the review will discuss strategies for enhancing the safety and optimize the management of AAV-based gene therapy that is emerging as an efficacious therapeutic option for disparate, severe, and often orphan conditions.
2024-06-26 | Novel mechanisms of action of emerging therapies of hereditary thrombotic thrombocytopenic purpura.
Hereditary thrombotic thrombocytopenic purpura (hTTP) is caused by deficiency of plasma ADAMTS13 activity, resulting from ADAMTS13 mutations. ADAMTS13 cleaves ultra large von Willebrand factor (VWF), thus reducing its multimer sizes. Hereditary deficiency of plasma ADAMTS13 activity leads to the formation of excessive platelet-VWF aggregates in small arterioles and capillaries, resulting in hTTP. PubMed search from 1956 to 2024 using thrombotic thrombocytopenic purpura and therapy identified 3,675 articles. Only the articles relevant to the topic were selected for discussion, which focuses on pathophysiology, clinical presentations, and mechanisms of action of emerging therapeutics for hTTP. Current therapies include infusion of plasma, or coagulation factor VIII, or recombinant ADAMTS13. Emerging therapies include anti-VWF A1 aptamers or nanobody and gene therapies with adeno-associated viral vector or self-inactivated lentiviral vector or a sleeping beauty transposon system for a long-term expression of a functional ADAMTS13 enzyme. Frequent plasma infusion remains to be the standard of care in most parts of the world, while recombinant ADAMTS13 has become the treatment of choice for hTTP in some of the Western countries. The success of gene therapies in preclinical models may hold a promise for future development of these novel approaches for a cure of hTTP.
2024-03-25 | Targeted ADAMTS-13 replacement therapy for thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic disorder associated with a severe deficiency of ADAMTS-13-the protease that cleaves von Willebrand factor. Plasma therapy is the current standard of care for managing acute episodes of TTP, which involves removing patient plasma and replacing it with donor plasma to raise the level of ADAMTS-13 activity. Recently, therapies aimed at replacing ADAMTS-13 have been investigated as possible substitutes or add-ons to plasma therapy for congenital and immune-mediated TTP. Enzyme replacement therapy provides recombinant ADAMTS-13 via intravenous (i.v.) infusion to restore enzyme activity. Recombinant ADAMTS-13-loaded platelets localize to the site of thrombus formation in a more concentrated manner than enzyme replacement or plasma therapy. ADAMTS-13-encoding messenger RNA aims to induce a steady supply of secreted protein and gene therapy is a potentially curative strategy. Overall, targeted ADAMTS-13 replacement therapies may provide better outcomes than plasma therapy by achieving higher levels of ADAMTS-13 activity and a more sustained response with fewer adverse events. Herein, we describe targeted ADAMTS-13 replacement therapies for the treatment of TTP and discuss the advantages and limitations of each approach.
small molecules
2026-06-24 | N-acetylcysteine in Thrombotic Thrombocytopenic Purpura: A Systematic Review.
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy characterized by severe ADAMTS13 deficiency and accumulation of ultralarge von Willebrand factor multimers. Although therapeutic plasma exchange (PEX), corticosteroids, rituximab, and caplacizumab have improved outcomes, refractory and relapsing disease remain important clinical challenges. N-acetylcysteine (NAC) has been explored as an adjunctive therapy because of its ability to reduce disulfide bonds within von Willebrand factor multimers. This systematic review aimed to summarize the published clinical experience with NAC in TTP, including treatment strategies, reported outcomes, and safety. A systematic search of PubMed was performed from database inception until December 31, 2025, using combinations of the terms "thrombotic thrombocytopenic purpura", "TTP", "N-acetylcysteine", and "acetylcysteine". Two reviewers independently screened records, assessed full texts against predefined eligibility criteria, and extracted study-level data. Eligible studies included case reports and case series describing therapeutic NAC use in patients with TTP. The review was conducted in accordance with PRISMA 2020 guidance. The protocol was not prospectively registered. Six publications comprising 22 adult patients were included. NAC was used as adjunctive therapy, predominantly in refractory or relapsing TTP, alongside PEX, corticosteroids, rituximab, and/or other immunosuppressive therapies. Platelet recovery was reported following NAC initiation in the included cases, with concurrent improvement in hemolysis markers and neurologic symptoms described in some reports. No serious NAC-related adverse events were reported in the included cases. Because all evidence was derived from uncontrolled reports with concomitant therapies, the independent contribution of NAC cannot be established. The available case-based literature suggests that NAC is a biologically plausible and generally well-tolerated adjunctive therapy in refractory or relapsing TTP. However, the current evidence remains hypothesis-generating and is insufficient to establish efficacy. Prospective studies are needed to clarify its therapeutic role, optimal dosing, and patient selection.
2026-06-24 | NETs contribute to acute episodes but not ADAMTS13 relapses in immune-mediated thrombotic thrombocytopenic purpura.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) results from acquired severe deficiency of a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13 (ADAMTS13). Neutrophil extracellular traps (NETs) contribute to acute iTTP episodes, but their role across different clinical stages and treatment modalities remains unclear. We conducted a retrospective, observational study in 8 patients with iTTP followed up for 7.4 years (range, 0.4-15.2). Patients experienced 8 first acute episodes (3 caplacizumab treated), 14 ADAMTS13 relapses, and 6 clinical relapses (2 caplacizumab treated), interjected by remissions. Besides clinical and ADAMTS13 parameters, we measured NET markers, including circulating DNA, myeloperoxidase (MPO), neutrophil elastase, and citrullinated histone H3. All NET markers were elevated at presentation with acute iTTP episodes and rapidly declined during treatment. The magnitude of NET marker reduction 3 days after treatment initiation was similar with and without caplacizumab (DNA, -61% ± 21% vs -49% ± 23%; MPO, -15% ± 49% vs -46% ± 33%). In the second week, patients treated without caplacizumab presented with another NET marker surge, paralleled by a drop in platelet counts; both were absent in caplacizumab-treated patients. NET levels remained unchanged during ADAMTS13 relapses compared to remission (DNA, 1.1-fold; MPO, 1.1-fold), whereas increases were documented in overt clinical relapses (DNA, 4.3-fold; MPO, 3.2-fold). Our findings indicate NET involvement in acute iTTP pathophysiology but suggest that NET formation requires a secondary trigger beyond ADAMTS13 deficiency. The second wave of NET formation and renewed platelet decline may be driven by von Willebrand factor-platelet interactions, as the phenomenon is absent in caplacizumab-treated patients. Our data support the benefit of preemptive immunosuppressive treatment for ADAMTS13 relapses.
2026-06-10 | Autophagy, NET formation, and inflammation crosstalk in thrombotic autoimmune diseases.
Neutrophil extracellular traps (NETs), released by activated neutrophils, are essential components of innate immunity, capturing and neutralizing pathogens. Dysregulated NET formation can both initiate and perpetuate inflammation, autoimmunity, and thrombosis. When NETs are excessively produced or insufficiently cleared, they expose autoantigens, fuel cytokine and interferon responses, and induce endothelial damage. In addition, NETs promote platelet adhesion, activate coagulation, and impair fibrinolysis, thereby establishing them as central drivers of immune-mediated thrombotic pathology. This review focuses on three representative thrombotic autoimmune diseases, namely immune thrombocytopenia (ITP), heparin-induced thrombocytopenia (HIT), and immune-mediated thrombotic thrombocytopenic purpura (iTTP), in which pathogenic autoantibodies and persistent NETs contribute to both thrombocytopenia and thrombosis. In ITP, endothelial activation and excessive NET release are associated with increased thrombotic risk. In HIT, platelet factor 4 (PF4)-NET complexes enhance thrombus formation while showing resistance to DNase-mediated degradation. Lastly, in iTTP, elevated levels of NET components correlate with platelet consumption and disease severity. Autophagy emerges as a central regulatory mechanism that shapes NET formation and immune activation. While autophagy supports pathogen clearance and maintains immune homeostasis, its dysregulation can amplify NET formation, sustain chronic inflammation, and promote loss of tolerance. This review proposes an interconnected model in which autophagy, NETs, and inflammation mutually reinforce one another, thereby driving thrombotic autoimmune diseases. Furthermore, it explores pharmacological agents targeting autophagy as potential treatment approaches aimed at disrupting the autophagy-NET-inflammation crosstalk and restoring immune homeostasis.
2026-05-11 | Clinical presentation and treatment outcomes in a South African thrombotic thrombocytopenic purpura cohort with and without HIV.
HIV is the most common cause of secondary thrombotic thrombocytopenic purpura (TTP) in South Africa. To assess the clinical presentations and outcomes of patients treated for HIV-associated and idiopathic TTP. We conducted a retrospective cohort study of patients consecutively diagnosed with TTP from 2010 to 2020 at Groote Schuur Hospital. Patients were identified by reviewing hospital and Western Cape Blood Services records. Kaplan-Meier curves and log-rank tests were used to evaluate remission rates, both overall and by HIV status and treatment group. Logistic regression models were used to identify predictors of remission and relapse. One hundred and thirty-nine patients were included, 85.6% of whom were HIV positive. There were no significant differences in the TTP pentad features by HIV status. Most patients achieved remission (71.9%) with a median time of eight days. Remission occurred significantly earlier in those treated with fresh frozen plasma only, suggesting less severe disease (median = 8 days [interquartile range 6-10]), compared to those requiring plasma exchange, suggesting more severe disease (median = 12 days [interquartile range 8-22]). The overall mortality in the 10-year period was 38.9%, with 10.8% of the surviving patients relapsing after 6 months. There were no significant differences in remission status, time to remission, mortality or relapse by HIV status. All HIV-positive patients who relapsed had defaulted their antiretroviral therapy (ART). HIV status did not affect patient outcomes in our cohort. ART is important in preventing HIV-associated TTP and relapse.
2026-04-14 | N-Acetylcysteine Therapy in Thrombotic Thrombocytopenic Purpura: A Systematic Review and Critical Appraisal.
Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition resulting from a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, leading to the accumulation of ultra-large von Willebrand factor (vWF) multimers and widespread microvascular thrombosis. While therapeutic plasma exchange and immunosuppression have significantly improved response, refractory and relapsed disease are significant challenges. N-acetylcysteine (NAC) has emerged as a biologically plausible adjunctive therapy due to its potential to reduce disulfide bonds in vWF multimers. However, its clinical role is unclear. This systematic review aimed to evaluate the clinical evidence regarding the efficacy and safety of N-acetylcysteine in patients with immune-mediated TTP. Methods: We performed a systematic review in accordance with the PRISMA guidelines. PubMed/MEDLINE, Google Scholar, and ClinicalTrials.gov were searched until January 2026. Studies involving patients with immune-mediated TTP treated with NAC were included. Case reports, case series, and observational studies involving patients with immune-mediated TTP treated with NAC were included. Risk of bias was evaluated using adapted quality assessment tools. Results: Sixteen studies encompassing 69 patients met the inclusion criteria. Most reports were case reports or small case series; two were larger observational cohorts. NAC was predominantly used as adjunctive therapy in relapsed or refractory TTP. Dose regimens varied. Platelet recovery following NAC was reported within 1-15 days in responding cases. Predominantly positive haematological responses were observed in small series. Significant heterogeneity in patient populations, timing of initiation, concomitant therapies, and outcome reporting limited causal inference. Conclusions: The current evidence suggests that NAC has a biologically rational and potentially adjunctive value in TTP, particularly in refractory disease or resource-constrained settings. However, current data are largely heterogeneous and derived from low-level evidence. Well-designed prospective studies and randomized controlled trials are needed to determine whether NAC provides significant clinical benefit beyond standard therapy.
cell therapies
2026-08-06 | Reversal of refractory systemic lupus erythematosus-associated immune thrombotic thrombocytopenic purpura and cerebritis via optimized lymphoplasmapheresis: a case report and literature review.
Systemic lupus erythematosus (SLE) complicated by immune thrombotic thrombocytopenic purpura (iTTP) and lupus cerebritis is a severe clinical event. Standard therapeutic plasma exchange (TPE) frequently fails in this context due to a "rebound effect", as it clears circulating antibodies but spares the intravascular reservoir of autoreactive lymphocytes. A 30-year-old male presented with refractory SLE, severe iTTP (platelet count: 5.00 × 10^9/L; ADAMTS13 activity: 1.49%), and imaging-confirmed lupus cerebritis. The patient underwent a unique "A-B-A" treatment trajectory. While five sessions of standard TPE at an outside facility did not fully halt the hyper-regenerative hemolysis and CNS progression, the implementation of an optimized lymphoplasmapheresis (LPE) regimen at our center induced rapid hematological remission, progressive radiological resolution of brain lesions, and the alleviation of immune-mediated renal injury, culminating in restored renal function and decreased proteinuria. The optimized LPE protocol utilized a novel dual-parameter modulation (synchronizing blood drawing speed and hematocrit) to precisely extract the pathogenic lymphocyte-rich buffy coat without exacerbating anemia. Paired quantitative analysis of the patient's peripheral blood and LPE effluent provided direct evidence of substantial cytokine (e.g., IL-10, IL-8, TNF-α) clearance. This facilitated the rapid seroconversion of antinuclear and anti-dsDNA antibodies. Furthermore, this targeted cellular depletion reduced the required allogeneic replacement plasma volume by up to 50% compared with standard TPE, conserving blood bank resources. Optimized LPE may interrupt the autoimmune cascade by simultaneously reducing circulating humoral mediators and lymphocyte-rich cellular components. This single-case observation supports its potential as a resource-sparing rescue strategy for refractory autoimmune microangiopathy, although further validation is required.
2026-07-27 | Platelet Transfusion in Patients With Low ADAMTS13-Confirmed Thrombotic Thrombocytopenic Purpura Is Associated With Increased Mortality.
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by severe ADAMTS13 deficiency. Platelet transfusions are generally contraindicated but are often administered before TTP is recognized. To evaluate the association between platelet transfusion in the emergency department (ED) and outcomes in laboratory-confirmed TTP. We conducted a retrospective multicenter cohort study using the TriNetX Research Network (2014-2025). Adults presenting to the ED with ADAMTS13 activity < 10% who received plasma exchange within 48 h were included. The exposure was platelet transfusion within 24 h. The primary outcome was 30-day all-cause mortality; secondary outcomes included myocardial infarction (MI), stroke, intracranial hemorrhage, thrombosis, and ICU-level care. Propensity score matching (1:1) and Cox modeling were performed. Among 693 patients, 99 (13.9%) received platelet transfusion. After matching, platelet transfusion was associated with higher 30-day mortality (30.0% vs. 13.3%; OR 2.79, 95% CI 1.31-5.93; p = 0.008) and increased MI. In Cox analysis, platelet transfusion remained independently associated with mortality (adjusted HR 2.45, 95% CI 1.24-4.85). In confirmed TTP, early platelet transfusion was independently associated with increased short-term mortality, supporting recommendations to avoid platelet transfusion and emphasizing early recognition.
2026-07-26 | Real-time, Multidisciplinary Approach of Women With Pregnancy-Associated Thrombotic Microangiopathy.
Thrombotic microangiopathies (TMAs) occurring during pregnancy or the immediate postpartum period are a rare, and highly complex syndrome. Determination of the most appropriate therapeutic strategy remains challenging and requires individualized assessment. To support both diagnostic and therapeutic decision-making, a national multidisciplinary consultation committee [MCC] (titled "TMA and Pregnancy") was established in October 2023 under the auspices of the French National Reference Center for TMAs. The MCC is activated for a single case, on an emergency basis, and within 24 hours. It brings together national experts from 8 medical specialties. Here, we report on 2 years of experience of the MCC, including operational aspects, activity indicators, the clinical and obstetrical profiles of the first 76 women whose cases were reviewed, the suspected diagnoses, and the real-time impact on patient management. Of the women, 29 (38%) were primiparous. The obstetrical context was preeclampsia in 47% and peripartum hemorrhage (PPH) in 40% of the women. TMA was most frequently attributed to severe endotheliosis, with acute kidney injury (AKI) present in 47 women (62%), including 9 (12%) showing renal cortical necrosis (RCN). Thrombotic thrombocytopenic purpura (TTP) was relatively uncommon (n = 13, 17%), and no cases were considered to represent atypical hemolytic and uremic syndrome (aHUS). The MCC led to a change in management in 26% of cases, most often a deescalation of therapy. We emphasize the value of real-time multidisciplinary case conferences in managing catastrophic obstetrical syndromes and advocate for the recognition of extreme phenotypes of endotheliosis extending beyond the liver. These findings underscore the need for therapies targeting endothelial injury.
2026-07-01 | Redefining Limits: Extracorporeal Cardiopulmonary Resuscitation in Adult Thrombotic Thrombocytopenic Purpura.
Thrombotic thrombocytopenic purpura (TTP) is a rare hematologic emergency that can rapidly progress to multiorgan failure and death if untreated. The role of extracorporeal membrane oxygenation (ECMO) in this setting is limited, and extracorporeal cardiopulmonary resuscitation (ECPR) has not been previously described. We report a case of a pregnant woman with suspected TTP who developed refractory pulseless electrical activity cardiac arrest before initiation of plasma exchange. Extracorporeal cardiopulmonary resuscitation with venoarterial ECMO was initiated despite profound thrombocytopenia (platelets 8,000/μL) as a bridge to definitive therapy, with rapid recovery of cardiac and renal function. She achieved full neurologic recovery and was discharged home without functional deficits. This case highlights the potential role of ECPR as a life-saving bridge in selected patients with TTP despite severe thrombocytopenia.
2026-04-16 | Establishing reverse chimeric antigen receptor T cells for precise targeting of immunemediated thrombotic thrombocytopenic purpura.
Immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP) is a life-threatening autoimmune disorder caused by autoantibodies that target the metalloprotease ADAMTS13. This prevents the cleavage of Ultra-Large von Willebrand Factor (UL-VWF), thereby forming microthrombi in the microvasculature. While current treatments are effective, ADAMTS13 relapses occur in up to 15% of the patients after rituximab administration. In this study, we propose a novel approach addressing the unmet need for treatment of patients with ADAMTS13 refractoriness and for patients requiring repeated treatment. Our strategy involves developing two targeted therapies that aim to achieve highly effective and safe B cell depletion. For the first time, we employ adapter Chimeric Antigen Receptor (CAR) T cells called Reverse CAR (RevCAR) T cells to (i) achieve a broader and deeper B cell depletion by targeting CD19 and (ii) selectively deplete the disease-causing anti-ADAMTS13 autoreactive B cells to increase precision and safety in iTTP treatment. Therefore, we have developed novel Target Modules (RevTMs) against CD19+ and anti-ADAMTS13 autoreactive B cells. We show that the RevCAR T cells successfully and specifically kill target hybridomas and Nalm-6 cells in a RevTM-dependent manner and at low effector-to-target cell ratios. Moreover, the RevCAR T cells are able to eliminate the target cells even in the presence of high concentrations of ADAMTS13 autoantibodies. Overall, our findings demonstrate for the first time, a proof-ofconcept that anti-ADAMTS13 autoreactive B cells can be selectively depleted by the RevCAR T cell platform paving the way for an effective and safe therapy for iTTP.
proteins
2026-09-07 | ADAMTS-13 fusion constructs with dual activity against von Willebrand factor: a novel strategy for immune-mediated thrombotic thrombocytopenic purpura.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy. iTTP pathophysiology stems from severe a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS-13) deficiency caused by autoantibodies, leading to accumulation of ultralarge von Willebrand factor (VWF) multimers and microvascular thrombosis. Engineered ADAMTS-13 variants reduce autoantibody binding. However, some show impaired VWF-cleaving activity, whereas others, such as glycan-engineered variants, retain proteolytic function. To investigate the AU/VWFa-11 (aVWF) single-domain antibody (sdAb) targeting the A1 domain of VWF in its active conformation, and 2 dual-action fusion constructs linking the sdAb to either a truncated ADAMTS-13 (Metalloprotease, Disintegrin, Thrombospondin type 1 repeat, Cysteine-rich and Spacer domains [MDTCS]; MDTCS-aVWF) or an autoantibody-resistant mutant (MDTCSm; MDTCSm-aVWF). Binding of aVWF to active VWF and the VWF A1 domain was assessed by enzyme-linked immunosorbent assays. Proteolytic activity was assessed using fluorescence resonance energy transfer substrate (FRETS)-VWF73, VWF multimer, and beads-on-a-string assays. VWF-platelet interactions were measured by light transmission aggregometry and flow cytometry. Autoantibody resistance was evaluated using FRETS-VWF73 assays in the presence of plasma from iTTP patients. aVWF sdAb selectively bound active VWF and inhibited platelet-VWF interactions in solution without impairing platelet adhesion to collagen-bound VWF. Both MDTCS-aVWF and MDTCSm-aVWF retained high proteolytic activity against VWF and reduced platelet-VWF interactions. Notably, MDTCSm-aVWF showed enhanced proteolytic activity and greater resistance to iTTP autoantibodies. The fusion construct MDTCSm-aVWF, which combines an enzymatically active, autoantibody-resistant ADAMTS-13 variant with a VWF conformation-specific inhibitory sdAb, offers a novel alternative therapeutic approach for iTTP.
2026-07-29 | Case Report: Albumin combined with plasma exchange in the treatment of refractory thrombotic thrombocytopenic purpura.
This study aims to analyze the clinical characteristics and causes of misdiagnosis in patients with thrombotic thrombocytopenic purpura (TTP) presenting with initial neurological symptoms, so as to provide reference for reducing misdiagnosis; to explore the feasibility and efficacy of albumin combined with plasma exchange in the treatment of TTP patients when plasma inventory is insufficient; and to put forward key precautions for TTP diagnosis and treatment, so as to provide strategic support for the treatment of similar cases. Clinical data of the patient (medical history, examination results, diagnosis and treatment records, etc.) were collected retrospectively; albumin combined with plasma exchange was adopted when plasma inventory was insufficient; laboratory indicators and symptom recovery were dynamically monitored to evaluate the effectiveness and safety of the treatment; misdiagnosis risks and the current status of alternative treatment were analyzed combined with literature review. Thrombotic thrombocytopenic purpura with initial neurological symptoms is easily confused with cerebral infarction, and thrombocytopenia of unknown origin is a key clue for differential screening. TTP should be excluded before platelet transfusion; when plasma inventory is insufficient, albumin combined with plasma exchange is feasible and effective for the treatment of AB-blood-type TTP, which can provide an alternative strategy for clinical practice; early diagnosis, timely targeted treatment and multidisciplinary collaboration are the keys to improving the prognosis of TTP patients.
2026-02-16 | Genetics of thrombotic thrombocytopenic purpura: systematic review in immune and congenital thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by severe deficiency of the metalloprotease ADAMTS13. TTP has 2 subtypes: immune (iTTP) and congenital (cTTP). Autoimmune mechanisms underlie iTTP; however, the genetic factors influencing disease risk, relapse risk, and response to treatment are incompletely understood. In cTTP, although variants are described throughout the ADAMTS13 gene, the effect of many of these variants is uncertain. We conducted a comprehensive literature review of both iTTP and cTTP, incorporating findings from genome-wide association studies, case-control studies, registry publications, and population-level databases. In iTTP, 9 studies have investigated the effect of HLA alleles, with HLA-DRB1∗11 most consistently associated with an increased risk, and HLA-DRB1∗04 with protection. However, effect sizes varied across ancestral populations, as we highlight in a meta-analysis of available studies. Beyond the HLA locus, a genome-wide association study in iTTP patients with European ancestry identified a locus on chromosome 3 (rs9884090) associated with a reduced iTTP risk. In cTTP, we identified 364 variants within the literature, the majority (199, 54.7%) being missense variants within coding regions. Although variants are located across the gene, the highest density of variants was observed within exon 7 (32 variants, 8.8% of the total), corresponding to the metalloprotease domain. Finally, analysis of population-level constraint data from gnomAD offered additional insight into the tolerance of ADAMTS13 to variation. Together, these findings highlight the complexity of the genetic factors influencing TTP, and the value of combining clinical information and population data to increase understanding of the disease.
2026-01-31 | Pathogen-reduced plasma, cryoprecipitate reduced for therapeutic plasma exchange.
Therapeutic plasma exchange (TPE) for thrombotic thrombocytopenic purpura (TTP) and auto-immune disorders involves repeated patient exposure to allogenic plasma with the risk of transfusion-transmitted infection (TTI). Amotosalen-UVA Pathogen Reduction technology is FDA approved to manufacture pathogen-reduced plasma, cryoprecipitate reduced (PRPCR), a form of cryoprecipitate poor plasma (CPP) with potentially improved TPE outcomes and reduced TTI risk. PRPCR was manufactured from pathogen-reduced (PR) plasma. Thrombin generation, fibrinogen, Factors II, V, VII, VIII, IX, X, XI, XIII, VWF, ADAMTS13, Protein C, Protein S, α-2 plasmin inhibitor (α-2 PI), IgG, IgM, and IgA were measured. Microfluidic chamber assays at variable shear rates characterized PRPCR-mediated platelet adhesion and aggregation. Compared to PR plasma, fibrinogen, Factor VIII, and VWF levels were depleted in PRPCR. Factors II, V, VII, IX, X, XI, XIII, thrombin generation, Protein C, Protein S, α-2 PI, ADAMTS13, and immunoglobulins were conserved. At low wall shear rates (300 s-1) PRPCR supported platelet adhesion. Perfusion of plasma-free blood containing PRPCR flowed over immobilized VWF binding peptide (100 μg/mL) and showed absence of platelet adhesion. Perfusion of plasma-free blood containing PRPCR flowed over immobilized collagen (200 μg/mL) at high wall shear rate (1500 s-1) and demonstrated no platelet thrombus formation. PRPCR retained hemostatic capacity, anti-thrombotic proteins, and ADAMTS13, but collagen induced platelet aggregation was negligible at high shear due to depletion of functional high molecular weight VWF. PRPCR is a CPP option for TPE with reduced platelet-mediated thrombotic risk and TTI risk, but with retention of plasma hemostatic capacity and immunoglobulins.
2025-12-14 | Thrombotic thrombocytopenic purpura following allogeneic hematopoietic stem cell transplantation: a rare but fatal complication.
Thrombotic microangiopathy (TMA) is a common and potentially fatal complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Thrombotic thrombocytopenic purpura (TTP), a distinct form of TMA caused by severe deficiency of plasma ADAMTS-13 activity, has been reported to be rare in the posttransplant population. To investigate the clinical features and outcomes of TTP after allo-HSCT. This retrospective cohort study used a nested case‒control approach. For each patient with TTP, 3 patients with high-risk transplant-associated TMA (TA-TMA) were matched as controls according to the time of transplantation. A total of 26 patients with TTP were identified and included in the cohort. Compared with patients with high-risk TA-TMA, patients with TTP had greater proportions of central nervous system (50.0% vs 19.2%, P = .002) and gastrointestinal tract involvement (65.4% vs 32.1%, P = .003), with central nervous system dysfunction occurring later (8.0 days vs -1.0 days since the diagnosis of TTP, P = .008). Patients with TTP had a significantly lower overall survival rate than those with high-risk TA-TMA (26.9% vs 48.7%, log-rank P = .026). Age >40 years at the time of TTP diagnosis was identified as an independent predictor of 60-day overall survival. TTP occurring in the setting of HSCT is rare but can be differentiated from TA-TMA and is associated with a worse prognosis.
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2026-09-23 | Cerebral Small Vessel Disease in Immune-Mediated Thrombotic Thrombocytopenic Purpura Patients During the Acute Phase and Disease Remission.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy characterized by acute neurological manifestations and long-term sequelae related to microvascular brain injury. Cerebral small vessel disease (cSVD), detectable on MRI through lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces, is a risk factor for stroke and cognitive decline, but its prevalence and evolution in iTTP are unknown. We conducted a prospective study of consecutive patients with acute iTTP and age-matched controls to assess the prevalence and one-year progression of cSVD. Brain MRI was performed at enrollment and repeated after 12-18 months in clinical remission. cSVD burden was quantified using a standardized 0-4 score based on four MRI markers. Twenty-five patients (median age 56 years; 60% women) were enrolled. Acute focal ischemic lesions were detected in 13 (52%). cSVD was present in 48% of patients versus 27% of controls, while moderate burden (score ≥ 2) occurred in 24% versus none. Ordinal logistic regression showed an association between iTTP and higher cSVD scores (OR 3.19, 95% CI 1.00-10.14), independent of traditional cardiovascular risk factors. Follow-up MRI was available in 22 patients (88%). In paired analyses, cSVD prevalence increased from 50% to 64%, moderate-to-high burden from 27% to 41%, and six patients (27%) showed score progression. At 1 year, patients had higher odds of greater cSVD burden than controls (age- and sex-adjusted ordinal OR 7.00, 95% CI 1.65-29.74). These findings indicate that cSVD is common during acute iTTP and progresses during the first year despite hematological remission.
2026-09-15 | Unintended Interruption of Caplacizumab Therapy Can Compromise Outcomes in Immune-Mediated Thrombotic Thrombocytopenic Purpura: Lessons from Two Clinical Cases.
Background: Caplacizumab is a cornerstone in the management of immune-mediated thrombotic thrombocytopenic purpura (iTTP), in combination with plasma exchange (PEX) and immunosuppression. Pivotal trials and real-world data have demonstrated faster platelet count recovery and improved remission rates. Nevertheless, a subset of patients still experiences exacerbations or delayed response. Observational evidence suggests that unintended treatment interruptions may contribute to these unfavorable outcomes. Methods: We report on two patients with iTTP treated with caplacizumab and immunosuppression; PEX was used in Case 1 and as escalation therapy in Case 2. Laboratory parameters including platelet count, lactate dehydrogenase (LDH), ADAMTS13 activity, and anti-ADAMTS13 autoantibodies were monitored. Results: In the first case, a 29-year-old female experienced an exacerbation and ischemic complications after two individual caplacizumab doses were unintentionally missed on days 12 and 14. Subsequent continuous administration led to stabilization and recovery. In the second case, a 42-year-old male presented with hemolytic anemia, thrombocytopenia, and ADAMTS13 activity of 1% and was initially treated with prednisolone and caplacizumab without PEX. Two individual caplacizumab doses were unintentionally missed on days 3 and 5 and were followed by delayed treatment response and microembolic infarcts. Treatment escalation to PEX and rituximab and reinitiation of continuous caplacizumab administration led to clinical stabilization. Conclusions: Even brief interruptions of caplacizumab therapy may compromise outcomes in iTTP. Continuous administration and secured availability, together with serial monitoring of ADAMTS13 activity to guide treatment duration and discontinuation, are essential to improve patient care.
2026-09-13 | Case report: Caplacizumab without plasma exchange for severe thrombotic thrombocytopenic purpura.
A 45-year-old female Jehovah's Witness presented with transient expressive aphasia, blurred vision, and dizziness for several hours. A complete blood count (CBC) showed anemia (hemoglobin: 6.3 g/dL), thrombocytopenia (platelet count: 21 × 103/µL), and undetectable haptoglobin. The peripheral smear revealed schistocytes, confirming microangiopathic hemolytic anemia; immune-mediated thrombotic thrombocytopenic purpura (iTTP) was confirmed with an ADAMTS13 level of less than 5% and a positive ADAMTS13 inhibitor screen. Treatment with high-dose corticosteroids was urgently initiated, but the patient and her husband declined plasma exchange based on their beliefs as Jehovah's Witnesses. The patient acutely decompensated, requiring intubation, with worsening of laboratory values (hemoglobin: 3.8 g/dL; platelet count: 9 × 103/µL), elevated serum troponin, and renal and hepatic compromise. In addition to rituximab and intravenous immune globulin, caplacizumab therapy was undertaken. The patient's condition improved clinically, but from a laboratory value perspective, 1 month after caplacizumab initiation, her ADAMTS13 level remained less than 5%. Further immunosuppression with intravenous cyclophosphamide was initiated, which resulted in complete normalization of ADAMTS13 activity. This is the first report of caplacizumab use in a Jehovah's Witness patient with TTP with severe neurological compromise to the point of necessitating intubation and with this degree of anemia. With the eventual addition of cyclophosphamide therapy, we observed complete recovery of this critically ill patient without the use of plasma exchange in the treatment course.
2026-09-08 | Evidence for the use of anti-CD20 therapeutic antibodies in immune thrombotic thrombocytopenic purpura management: a review.
Immune thrombotic thrombocytopenic purpura (iTTP) is an autoimmune thrombotic microangiopathy caused by antibody-mediated deficiency of the plasma metalloprotease ADAMTS13. Therapeutic antibodies that target antibody-producing B-cells via the CD20 surface receptor protein to prevent disease exacerbation and relapse have become part of the standard of care of patients with iTTP. However, clinical trial data regarding the use of anti-CD20 agents is limited to mostly phase II studies; no universally agreed-upon standardized protocol for the use of CD20-targeting antibodies for iTTP regarding choice of agent, dosage, or duration of treatment exists; refractoriness or lack of response to anti-CD20 antibodies can occur; and several agents and biosimilars are now available for the treatment of iTTP patients, which complicates the decision tree for clinicians caring for these patients. In this review, we explore the current landscape of anti-CD20 therapeutics used to treat iTTP, focusing on agents currently available for clinical use. We describe the pharmacokinetic and pharmacodynamic properties of CD20-targeting antibodies; available data regarding dosage and duration of treatment; anti-CD20 antibody therapy refractoriness or lack of response; and the evolving role of anti-CD20 biosimilars. This review will shed light on the state-of-the-art in CD20-targeting antibodies used to treat iTTP patients with an eye toward identifying areas in need of further study to aid in the care of patients with this rare and often devastating disease.
2026-09-01 | Refractory Acquired Thrombotic Thrombocytopenic Purpura in the Third Trimester of Twin Pregnancy: A Case Report
Background: Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening condition triggered by pregnancy, often in the third trimester, and frequently mimics preeclampsia or HELLP syndrome due to shared features like thrombocytopenia. Refractory cases in twin pregnancies, described in this case, pose unique diagnostic and therapeutic challenges, requiring advanced interventions. Case Presentation: A 29-year-old woman carrying dichorionic-diamniotic twins presented in the third trimester with palpitations, dyspnea, oral bleeding, numbness, chest heaviness, fatigue, edema, and pelvic pain. Admission showed severe thrombocytopenia (8 × 10 9 /L), microangiopathic hemolytic anemia (schistocytes, elevated LDH), normal blood pressure, and normal liver/kidney function, making preeclampsia/HELLP unlikely. Because of the high bleeding risk posed by the profound thrombocytopenia, and despite a reassuring fetal assessment, an emergency cesarean section was performed and delivered two healthy baby girls with good Apgar scores. ADAMTS13 activity < 10% subsequently confirmed acquired TTP. Plasma exchange and corticosteroids were started presumptively on the day of admission; because the platelet response was incomplete, rituximab and caplacizumab were added during the same admission. The patient was discharged after initial hematologic recovery but relapsed with recurrent severe thrombocytopenia three days later, confirming refractory disease; she was readmitted and achieved sustained platelet normalization with continued plasma exchange, rituximab, and caplacizumab. Complications included wound infection with multiple organisms, antibiotic allergy, and superficial venous thrombosis, all managed successfully. Both mother and infants were discharged well, with no further relapse at six-week follow-up. Future pregnancies were discouraged without specialist review. Conclusions: High suspicion for TTP is essential in pregnant patients with thrombocytopenia and hemolysis, even without hypertension. Rapid ADAMTS13 testing, timely delivery, and combined plasma exchange with rituximab and caplacizumab enabled full recovery in this refractory twin-pregnancy case. Multidisciplinary care is critical to differentiate from obstetric mimics and achieve favorable outcomes. Keywords: TTP, twin pregnancy, ADAMTS13, caplacizumab, case report
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2026-09-14 | Immune Thrombotic Thrombocytopenic Purpura Presenting as an Acute Stroke Mimic in a Young Pakistani Man.
Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy that can have acute neurological symptoms and resemble ischemic stroke. A 27-year-old Pakistani man was transported by ambulance after being found unconscious, unable to speak, and unable to move his right side, which was suspected to be a stroke. He had been unwell for two weeks, was clinically jaundiced, and had a possible seizure during the previous week. Urgent plain computed tomography (CT) and CT angiography of the brain were called and revealed no acute abnormality and no obvious large vessel occlusion. There was no evidence of acute infarction on magnetic resonance imaging. His National Institutes of Health Stroke Scale (NIHSS) score was 15/42, which is a moderate stroke. Laboratory studies showed hemoglobin 6.0 g/dL, platelet count 3x109/L, schistocytes on peripheral smear, lactate dehydrogenase 2139 U/L, haptoglobin <0.01 g/L, reticulocytosis, and mainly indirect hyperbilirubinemia. The clinical features were compatible with iTTP complicated with neurological involvement. The patient was treated with therapeutic plasma exchange daily, high-dose methylprednisolone, and rituximab. Platelets rose steadily to 199x109/L on day 8, bilirubin levels dropped to 14.2 µmol/L, and lactate dehydrogenase levels dropped to 259 U/L at discharge. Neurological recovery was quick, with resolution of the right-sided weakness by the fourth hospital day and an NIHSS score of 0. This case highlights that in young patients with stroke-like presentation, severe thrombocytopenia, and microangiopathic hemolytic anemia, prompt plasma exchange and immunosuppression can be lifesaving and should be considered in iTTP.
2026-07-09 | Update in treatment options for congenital and immune thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy resulting either from congenital deficiency (cTTP) or acquired (immune) deficiency (iTTP) of A Disintegrin and Metalloprotease with ThromboSpondin-type 1 motif, member 13 (ADAMTS13). Deficiency of ADAMTS13 leads to disseminated platelet thrombosis and organ dysfunction. High mortality of cTTP is prevented by plasma infusion to replace the deficient protease, or more recently by infusion of recombinant ADAMTS13. Standard treatment of iTTP includes steroids, plasma exchange, and rituximab, with or without caplacizumab. Although standard treatment of iTTP improves mortality, refractory cases persist, indicating the need for additional treatment options. This review summarizes the status of novel treatment options for cTTP and iTTP, including additional recombinant ADAMTS13 products, ADAMTS13 gene therapies, plasma cell-directed therapies (bortezomib, daratumumab) as well as novel inhibitors of von Willebrand factor activity.
2024-09-12 | Emerging Thrombotic Disorders Associated with Virus-Based Innovative Therapies: From VITT to AAV Gene Therapy-Related Thrombotic Microangiopathy.
Gene therapy is a promising therapeutic approach for treating life-threatening disorders. Despite the clinical improvements observed with gene therapy, immune responses either innate or adaptive against the vector used for gene delivery, can affect treatment efficacy and lead to adverse reactions. Thrombotic microangiopathy (TMA) is a thrombosis with thrombocytopenia syndrome (TTS) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and small vessel occlusion known to be elicited by several drugs, that has been recently reported as an adverse event of adeno-associated virus (AAV)-based gene therapy. TMA encompasses a heterogenous group of disorders, its classification and underlining mechanisms are still uncertain, and still lacks validated biomarkers. The identification of predictors of TMA, such as vector dose and patient characteristics, is a pressing need to recognize patients at risk before and after AAV-based gene therapy administration. This review aims to explore the literature on TMA associated with AAV-based gene therapy in the larger context of TMA (i.e., hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, and other drug-related TMAs). Considering the wide attention recently gained by another TTS associated with a non-gene therapy viral platform (adenovirus, AV COVID-19 vaccine), namely vaccine-induced immune thrombocytopenia and thrombosis (VITT), AAV gene therapy-related TMA mechanisms will be discussed and differentiated from those of VITT to avoid recency bias and favor a correct positioning of these two recently emerged syndromes within the heterogenous group of drug-related TTS. Finally, the review will discuss strategies for enhancing the safety and optimize the management of AAV-based gene therapy that is emerging as an efficacious therapeutic option for disparate, severe, and often orphan conditions.
2024-06-26 | Novel mechanisms of action of emerging therapies of hereditary thrombotic thrombocytopenic purpura.
Hereditary thrombotic thrombocytopenic purpura (hTTP) is caused by deficiency of plasma ADAMTS13 activity, resulting from ADAMTS13 mutations. ADAMTS13 cleaves ultra large von Willebrand factor (VWF), thus reducing its multimer sizes. Hereditary deficiency of plasma ADAMTS13 activity leads to the formation of excessive platelet-VWF aggregates in small arterioles and capillaries, resulting in hTTP. PubMed search from 1956 to 2024 using thrombotic thrombocytopenic purpura and therapy identified 3,675 articles. Only the articles relevant to the topic were selected for discussion, which focuses on pathophysiology, clinical presentations, and mechanisms of action of emerging therapeutics for hTTP. Current therapies include infusion of plasma, or coagulation factor VIII, or recombinant ADAMTS13. Emerging therapies include anti-VWF A1 aptamers or nanobody and gene therapies with adeno-associated viral vector or self-inactivated lentiviral vector or a sleeping beauty transposon system for a long-term expression of a functional ADAMTS13 enzyme. Frequent plasma infusion remains to be the standard of care in most parts of the world, while recombinant ADAMTS13 has become the treatment of choice for hTTP in some of the Western countries. The success of gene therapies in preclinical models may hold a promise for future development of these novel approaches for a cure of hTTP.
2024-03-25 | Targeted ADAMTS-13 replacement therapy for thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic disorder associated with a severe deficiency of ADAMTS-13-the protease that cleaves von Willebrand factor. Plasma therapy is the current standard of care for managing acute episodes of TTP, which involves removing patient plasma and replacing it with donor plasma to raise the level of ADAMTS-13 activity. Recently, therapies aimed at replacing ADAMTS-13 have been investigated as possible substitutes or add-ons to plasma therapy for congenital and immune-mediated TTP. Enzyme replacement therapy provides recombinant ADAMTS-13 via intravenous (i.v.) infusion to restore enzyme activity. Recombinant ADAMTS-13-loaded platelets localize to the site of thrombus formation in a more concentrated manner than enzyme replacement or plasma therapy. ADAMTS-13-encoding messenger RNA aims to induce a steady supply of secreted protein and gene therapy is a potentially curative strategy. Overall, targeted ADAMTS-13 replacement therapies may provide better outcomes than plasma therapy by achieving higher levels of ADAMTS-13 activity and a more sustained response with fewer adverse events. Herein, we describe targeted ADAMTS-13 replacement therapies for the treatment of TTP and discuss the advantages and limitations of each approach.
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Drug Discovery Landscape
16 orphan drug designations for Thrombotic thrombocytopenic purpura, including 5 approved therapies.
16 orphan drug designations for Thrombotic thrombocytopenic purpura, including 5 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
a fusion protein consisting of the catalytic domain of the human urokinase-type plasminogen activator (UPA) and an antibody fragment (variable heavy domain of a heavy chain antibody [VHH]), that binds with high affinity to the C-terminal cystine knot (CTCK) domain of VWF | proteins | FDA | TargED Biopharmaceuticals B.V. | |
Urokinase, catalytic domain, fused with a single-chain antibody against von Willebrand factor | combination | EMA | TargED Biopharmaceuticals B.V. | |
A (recombinant) disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) protein | proteins | FDA | — | GC Biopharma Corp. |
anfibatide | antibodies | FDA | Lee's Pharmaceutical (Hong Kong) Limited | |
S-59 treated FFP (plasma treated with amotosalen hydrochloride & ultraviolet A light | other | FDA | — | Cerus Corporation |
Nanobody directed towards the human A1 domain of von Willebrand factor [Cablivi] | antibodies | EMA | Approved | Ablynx N.V. |
Caplacizumab [CABLIVI] | antibodies | FDA | Approved | Ablynx, a wholly owned subsidiary of Sanofi Group |
caplacizumab-yhdp [Cablivi] | antibodies | FDA | Approved | Ablynx, a wholly owned subsidiary of Sanofi Group |
Recombinant human ADAMTS-13 [ADZYNMA] | proteins | EMA | Approved | Takeda Manufacturing Austria AG |
Recombinant disintegrin and metalloprotease with thrombospondin type 1 motifs | proteins | FDA | Takeda Development Center Americas, Inc. | |
ADAMTS13, recombinant-krhn [Adzynma] | proteins | FDA | Approved | Takeda Development Center Americas, Inc. |
Egaptivon pegol | oligonucleotides | EMA | FGK Representative Service GmbH | |
Anti-von Willebrand Aptamer | oligonucleotides | FDA | Archemix Corporation | |
solvent/detergent treated non-blood-group specific human coagulation active plasma | other | FDA | Octapharma USA, Inc. | |
Romiplostim [Nplate] | peptides | EMA | Amgen Europe B.V. | |
Defibrotide | oligonucleotides | FDA | — | Crinos International |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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