Von Willebrand factor (VWF) is an essential contributor to microvascular thrombosis. Physiological cleavage by ADAMTS13 limits its prothrombotic properties, explaining why ADAMTS13 deficiency leads ...to attacks of microthrombosis in patients with thrombotic thrombocytopenic purpura (TTP). We previously reported that plasminogen activation takes place during TTP attacks in these patients. Furthermore, stimulation of plasminogen activation attenuates pathogenesis in preclinical TTP models in vivo. This suggests that plasmin is an endogenous regulator of VWF thrombogenicity, in particular when ADAMTS13 falls short to prevent microvascular occlusions. VWF cleavage by plasmin is biochemically distinct from cleavage by ADAMTS13. We hypothesized that plasmin-cleaved VWF (cVWF) holds value as a biomarker of microvascular thrombosis. We developed a V HH-based bioassay that can distinguish cVWF from intact and ADAMTS13-cleaved VWF in plasma. We validate this assay by tracking cVWF release during degradation of microthombi in vitro. We demonstrate that endogenous cVWF formation takes place in TTP patients during acute attacks of thrombotic microangiopathy, but not in remission. Finally, we show that therapeutic plasminogen activation in a mouse model for TTP amplifies cVWF formation, which is accompanied by VWF clearance. Our combined findings indicate that cVWF is released from microthrombi in the context of microvascular occlusion.
There is ambiguity whether frail patients with atrial fibrillation managed with vitamin K antagonists (VKAs) should be switched to a non-vitamin K oral anticoagulant (NOAC).
We conducted a pragmatic, ...multicenter, open-label, randomized controlled superiority trial. Older patients with atrial fibrillation living with frailty (≥75 years of age plus a Groningen Frailty Indicator score ≥3) were randomly assigned to switch from international normalized ratio-guided VKA treatment to an NOAC or to continued VKA treatment. Patients with a glomerular filtration rate <30 mL·min
·1.73 m
or with valvular atrial fibrillation were excluded. Follow-up was 12 months. The cause-specific hazard ratio was calculated for occurrence of the primary outcome that was a major or clinically relevant nonmajor bleeding complication, whichever came first, accounting for death as a competing risk. Analyses followed the intention-to-treat principle. Secondary outcomes included thromboembolic events.
Between January 2018 and June 2022, a total of 2621 patients were screened for eligibility and 1330 patients were randomly assigned (mean age 83 years, median Groningen Frailty Indicator score 4). After randomization, 6 patients in the switch-to-NOAC arm and 1 patient in the continue-with-VKA arm were excluded due to the presence of exclusion criteria, leaving 662 patients switched from a VKA to an NOAC and 661 patients continued VKAs in the intention-to-treat population. After 163 primary outcome events (101 in the switch arm, 62 in the continue arm), the trial was stopped for futility according to a prespecified futility analysis. The hazard ratio for our primary outcome was 1.69 (95% CI, 1.23-2.32). The hazard ratio for thromboembolic events was 1.26 (95% CI, 0.60-2.61).
Switching international normalized ratio-guided VKA treatment to an NOAC in frail older patients with atrial fibrillation was associated with more bleeding complications compared with continuing VKA treatment, without an associated reduction in thromboembolic complications.
URL: https://eudract.ema.europa.eu; Unique identifier: 2017-000393-11. URL: https://eudract.ema.europa.eu; Unique identifier: 6721 (FRAIL-AF study).
Plasma Levels of Cellular Fibronectin in Diabetes
Suzan D.J.M. Kanters , MD, PHD ,
Jan-Dirk Banga , MD, PHD ,
Ale Algra , MD, PHD ,
Rini C.J.M. Frijns , MD ,
Jaap J. Beutler , MD, PHD and
Rob ...Fijnheer , MD, PHD
From the Department of Internal Medicine (S.D.J.M.K.,J.-D.B.), the Julius
Center for Patient-Oriented Research (A.A.), the Department of Neurology
(A.A., R.C.J.M.F.), the Department of Nephrology and Hypertension (J.J.B.),
and the Department of Hematology (R.F.), University Medical Center, Utrecht,
the Netherlands.
Address correspondence and reprint requests to Jan-Dirk Banga, MD, PhD,
Department of Internal Medicine, G02.228, University Medical Center Utrecht,
P.O. Box 85500, 3508 GA, Utrecht, the Netherlands. E-mail:
j.d.banga{at}digd.azu.nl
.
Abstract
OBJECTIVE — Cellular fibronectin is an endothelium-derived
protein involved in subendothelial matrix assembly. Elevated plasma levels of
cellular fibronectin therefore reflect loss of endothelial cell polarization
or injury to blood vessels. Consequently, elevated plasma levels of
circulating cellular fibronectin have been described in clinical syndromes
with vascular damage, although not in diabetes or atherosclerosis.
RESEARCH DESIGN AND METHODS — We determined fibronectin levels
in 52 patients with type 1 diabetes, 50 patients with type 2 diabetes, 54
patients with a history of ischemic stroke, 23 patients with renal artery
stenosis, and 64 healthy subjects.
RESULTS — Circulating cellular fibronectin was significantly
elevated in patients with diabetes (4.3 ± 2.8 μg/ml) compared with
patients with ischemic stroke (2.0 ± 0.9 μg/ml), patients with
renovascular hypertension (1.7 ± 1.1 μg/ml), and healthy subjects
(1.4 ± 0.6 μg/ml). Patients with diabetes and at least one
cardiovascular risk factor had an almost 2.5-fold increase in cellular
fibronectin compared with diabetic subjects without such a risk factor. In
multivariate regression analysis, higher triglycerides, current or past
cigarette smoking, and higher urinary albumin excretion were independently
associated with an increase in circulating cellular fibronectin in
diabetes.
CONCLUSIONS — These results suggest that circulating cellular
fibronectin may be a marker protein for endothelial cell activation,
especially in diabetes. Prospective studies are needed to explore this
possibility.
Footnotes
Abbreviations: BSA, bovine serum albumin; ED, extra domain; MoAb,
monoclonal antibody; PBS, phosphate-buffered saline; vWF, von Willebrand
factor.
A table elsewhere in this issue shows conventional and
Système International (SI) units and
conversion factors for many substances.
Accepted October 27, 2000.
Received July 10, 2000.
by the American Diabetes Association,
Inc.
BACKGROUND
The Gram‐negative bacillus Capnocytophaga canimorsus may cause a severe illness resembling thrombotic thrombocytopenic purpura (TTP). The pathogenesis and optimal therapy of this secondary ...thrombotic microangiopathy (TMA) remain uncertain.
CASE REPORT
A 63‐year‐old Caucasian man was admitted with suspicion for TTP, but blood cultures grew C. canimorsus. Initial investigations revealed severe thrombocytopenia, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity level of less than 1%, and strongly elevated D‐dimer and lactate dehydrogenase levels. He made a full recovery with antibiotics and plasma infusion for 3 days. Plasmapheresis was not performed. Retrospective determination of serial ADAMTS13 activity levels revealed that ADAMTS13 activity had already increased to 25% at the start of plasma infusion.
CONCLUSION
This case highlights that a C. canimorsus sepsis may cause a secondary TMA with a severe ADAMTS13 deficiency. It also illustrates that the adjunctive role of plasma exchange or plasma infusion is doubtful as ADAMTS13 activity levels increased with antibiotics alone.
ADAMTS-13 adopts an open conformation in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in acute phase while being closed in healthy donors. We reported that a substantial ...number of patients with iTTP in remission with restored ADAMTS-13 activity (>50%) still had an open ADAMTS-13 conformation, although a closed conformation is expected given the extent of remission.
To investigate whether open ADAMTS-13, represented by a conformation index >0.5, is associated with a risk of earlier ADAMTS-13 and/or clinical relapse.
We collected follow-up data (ADAMTS-13 parameters, ADAMTS-13 and clinical relapse, and treatment) from 81 patients with iTTP in remission with ADAMTS-13 activity >50%.
During follow-up, 19 ADAMTS-13 and 10 clinical relapses were reported (median follow-up period, 20 months). First, open or closed ADAMTS-13 conformation was dichotomized based on the 0.5 conformation index cutoff. Open ADAMTS-13 (conformation index, >0.5) was not identified as a risk factor for ADAMTS-13 and clinical relapse (log-rank test and Cox regression model). In contrast, by identifying the optimal conformation index cutoff for relapse prediction, using classification and regression tree analysis, a conformation index >0.645 and >0.835 was shown to be a risk factor for ADAMTS-13 relapse (hazard ratio, 3.3; 95% CI, 1.3-8.3; P = .01) and clinical relapse (hazard ratio, 4.4; 95% CI, 1.3-15.3; P = .02), respectively.
Patients with open ADAMTS-13 with a conformation index >0.645 and >0.835 have a >3- and >4-fold higher risk of earlier ADAMTS-13 and clinical relapse, respectively. Hence, ADAMTS-13 conformation index could be used to complement ADAMTS-13 activity monitoring to timely notice ADAMTS-13 relapse and prevent clinical relapse.
Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder resulting from the development of autoantibodies against ADAMTS13 (a disintegrin and metalloproteinase with a ...thrombospondin type 1 motif, member 13). HLA-DRB1*11 provides a risk factor for developing acquired TTP. Pulsing of antigen-presenting cells from HLA-DRB1*11– and HLA-DRB1*03–positive individuals with ADAMTS13 resulted in presentation of peptides derived from the CUB2 domain of ADAMTS13 with core sequences FINVAPHAR or ASYILIRD. Here, we assessed whether FINVAPHAR- or ASYILIRD-reactive CD4+ T cells are present in peripheral blood mononuclear cells from HLA-DRB1*11 and HLA-DRB1*03–positive subjects with acquired TTP. The presence of ADAMTS13-reactive CD4+ T cells was addressed by flow cytometry and the expression of activation marker CD40 ligand by CD4+ T cells. FINVAPHAR-reactive CD4+ T cells were identified in an HLA-DRB1*11–positive patient during the acute phase of the disease whereas ASYILIRD-positive CD4+ T cells were identified in a DRB1*03-positive patient with acquired TTP. Frequencies of CUB2 domain-reactive CD4+ T cells ranged from 3.3% to 4.5%. Control peptides in which the anchor residues were modified did not induce activation of CD4+ T cells. Taken together, our data provide evidence for the involvement of CUB2 domain-reactive CD4+ T cells in the etiology of acquired TTP.
•CD4+ T-cell responses in 2 patients with acquired TTP.•CUB2 domain-derived core peptides are recognized by CD4+ T cells present in 2 patients with acquired TTP.
Immunochemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become standard of care for patients with diffuse large B-cell lymphoma (DLBCL). This ...randomized trial assessed whether rituximab intensification during the first 4 cycles of R-CHOP could improve the outcome of these patients compared with standard R-CHOP.
A total of 574 patients with DLBCL age 18 to 80 years were randomly assigned to induction therapy with 6 or 8 cycles of R-CHOP-14 with (RR-CHOP-14) or without (R-CHOP-14) intensification of rituximab in the first 4 cycles. The primary end point was complete remission (CR) on induction. Analyses were performed by intention to treat.
CR was achieved in 254 (89%) of 286 patients in the R-CHOP-14 arm and 249 (86%) of 288 patients in the RR-CHOP-14 arm (hazard ratio HR, 0.82; 95% CI, 0.50 to 1.36;
= .44). After a median follow-up of 92 months (range, 1-131 months), 3-year failure-free survival was 74% (95% CI, 68% to 78%) in the R-CHOP-14 arm versus 69% (95% CI, 63% to 74%) in the RR-CHOP-14 arm (HR, 1.26; 95% CI, 0.98 to 1.61;
= .07). Progression-free survival at 3 years was 74% (95% CI, 69% to 79%) in the R-CHOP-14 arm versus 71% (95% CI, 66% to 76%) in the RR-CHOP-14 arm (HR, 1.20; 95% CI, 0.94 to 1.55;
= .15). Overall survival at 3 years was 81% (95% CI, 76% to 85%) in the R-CHOP-14 arm versus 76% (95% CI, 70% to 80%) in the RR-CHOP-14 arm (HR, 1.27; 95% CI, 0.97 to 1.67;
= .09). Patients between ages 66 and 80 years experienced significantly more toxicity during the first 4 cycles in the RR-CHOP-14 arm, especially neutropenia and infections.
Early rituximab intensification during R-CHOP-14 does not improve outcome in patients with untreated DLBCL.
Abstract The majority of the patients affected by acquired thrombotic thrombocytopenic purpura (TTP) develop autoantibodies directed towards ADAMTS13 that interfere with its von Willebrand Factor ...(VWF) processing activity. B cell responses have been shown to primarily target the spacer domain of ADAMTS13 thereby prohibiting the binding of ADAMTS13 to the VWF A2 domain. In this review we summarize recent knowledge gained on the immune recognition and processing of ADAMTS13 by antigen-presenting cells (APCs). HLA-DRB1*11 has been identified as a risk factor for acquired TTP. Analysis of MHC class II/peptide complexes of ADAMTS13 pulsed dendritic cells have shown that the CUB2 domain derived peptide FINVAPHAR is preferentially presented on HLA-DRB1*11. Based on these findings we propose a model for the initiation of the autoimmune reactivity against ADAMTS13 in previously healthy individuals. We hypothesize that mimicry between a pathogen-derived peptide and the CUB2 derived FINVAPHAR-peptide might contribute to the onset of acquired TTP.
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