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.
Glanzmann thrombasthenia (GT) is characterized by absent platelet aggregation in response to all agonists except ristocetin and is caused by recessive inactivating variants in ITGA2B or ITGB3. Although patients with GT typically are described as having normal platelet counts, autosomal dominant activating variants in ITGA2B or ITGB3 cause macrothrombocytopenia. Interestingly, in our cohort of 16 patients with GT, 8 consistently exhibited platelet counts at the lower end of the normal range. We studied the role of integrin a IIb R 3 in platelet formation using megakaryocytes (MKs) derived from genetically modified immortalized MK cell lines (imMKCLs), focusing on 2 modifications of ITGB3: ITGB3 -/- (inactivating) and ITGB3 WT/D673_E713del (activating). In static differentiation culbut reduced proplatelet formation. Platelet production was also impaired in a 3-dimensional silk-based bone marrow system and in shaking cultures, confirming a quantitative role for ITGB3 in platelet production independent of the type of variant. Although thrombin receptor activating protein-activated, in vitro-generated platelets lacking a IIb R 3 failed to bind the activation-dependent PAC-1 antibody, ITGB3 WT/D673_E713del platelets bound PAC-1 before activation, mimicking the patient's phenotype. Transcriptome profiling and metabolomic analyses of integrin a IIb R 3 -deficient MKs revealed impaired serine metabolism and downregulation of SLC3A2 (CD98hc), an amino acid transporter chaperon known to interact with the R 3 subunit. Flow cytometry confirmed decreased CD98hc in mutant MKs, whereas reexpression of wild-type ITGB3 in ITGB3 -/- MKs restored a IIb R 3 and CD98hc expression, normalized proplatelet formation, and enhanced serine uptake. These results uncover a previously unrecognized role of integrin a IIb R 3 in coupling serine metabolism to platelet biogenesis.
Host-versus-graft reaction (HVGR) is a major challenge in allogeneic chimeric antigen receptor (CAR) T-cell therapy. To counter host natural killer (NK) cell attacks, we armored allogeneic, HLA-I-deficient, B-cell maturation antigen (BCMA)-targeting CAR T cells with an NKG2A CAR. In vitro and animal studies demonstrated that allogeneic CAR-NKG2A T cells effectively resisted host NK cell-mediated killing. BCMA and NKG2A dual-targeting allogeneic CAR T cells (CT0590) resisted killing by NK cells and showed robust antitumor activity in preclinical in vivo models. On the basis of these data, a first-in-human study enrolled 5 patients (4 with relapsed and refractory multiple myeloma [RRMM] and 1 with primary plasma cell leukemia [pPCL]). CT0590 was well tolerated and caused no doselimiting toxicities, treatment-related death, or graft-versus-host disease. Three patients achieved confirmed responses, including 2 with stringent complete response (sCR). Notably, sCR in the patient with RRMM was still ongoing (duration of response >23 months) at the time of data cutoff, and sCR in the patient with pPCL lasted for 20 months. Both patients showed robust expansion of universal CAR T cells (maximum concentration of >280 000 copies per mu g genomic DNA) and higher baseline NKG2A expression on NK cells than nonresponders. These results suggest that CAR-NKG2A technology may overcome HVGR, especially in patients with elevated NKG2A expression on NK cells. Further studies of CT0590 in RRMM and pPCL are warranted. This trial was registered at www.clinicaltrials.gov as NCT05066022.
