Acquired thrombotic thrombocytopenic purpura (aTTP) is a thrombotic microangiopathy with a severe mortality and morbidity. Caplacizumab has recently been approved in the Netherlands as a new ...therapeutic option in patients with life-threatening organ failure due to aTTP. We describe the case of a 50 year old patient with aTTP who was referred to our hospital for treatment with caplacizumab. After undergoing treatment with plasmapheresis, prednisolone, rituximab and caplacizumab, her platelet count recovered and she was ready to be discharged. Unfortunately, before discharge she developed a fatal intra-cerebral hemorrhage. Fatal hemorrhage as an adverse event of caplacizumab has not been described before. Up to now there is no evidence-based treatment for caplacizumab induced heavy bleeding.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The risk of major bleeding complications in catheter directed thrombolysis (CDT) for acute limb ischemia (ALI) remains high, with reported major bleeding complication rates in up to 1 in every 10 ...treated patients. Fibrinogen was the only predictive marker used for bleeding complications in CDT, despite the lack of high quality evidence to support this. Therefore, recent international guidelines recommend against the use of fibrinogen during CDT. However, no alternative biomarkers exist to effectively predict CDT-related bleeding complications. The aim of the POCHET biobank is to prospectively assess the rate and etiology of bleeding complications during CDT and to provide a biobank of blood samples to investigate potential novel biomarkers to predict bleeding complications during CDT.
The POCHET biobank is a multicentre prospective biobank. After informed consent, all consecutive patients with lower extremity ALI eligible for CDT are included. All patients are treated according to a predefined standard operating procedure which is aligned in all participating centres. Baseline and follow-up data are collected. Prior to CDT and subsequently every six hours, venous blood samples are obtained and stored in the biobank for future analyses. The primary outcome is the occurrence of non-access related major bleeding complications, which is assessed by an independent adjudication committee. Secondary outcomes are non-major bleeding complications and other CDT related complications. Proposed biomarkers to be investigated include fibrinogen, to end the debate on its usefulness, anti-plasmin and D-Dimer.
The POCHET biobank provides contemporary data and outcomes of patients during CDT for ALI, coupled with their blood samples taken prior and during CDT. Thereby, the POCHET biobank is a real world monitor on biomarkers during CDT, supporting a broad spectrum of future research for the identification of patients at high risk for bleeding complications during CDT and to identify new biomarkers to enhance safety in CDT treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Thrombosis is a major clinical complication of COVID-19 infection. COVID-19 patients show changes in coagulation factors that indicate an important role for the coagulation system in the pathogenesis ...of COVID-19. However, the multifactorial nature of thrombosis complicates the prediction of thrombotic events based on a single hemostatic variable. We developed and validated a neural net for the prediction of COVID-19-related thrombosis. The neural net was developed based on the hemostatic and general (laboratory) variables of 149 confirmed COVID-19 patients from two cohorts: at the time of hospital admission (cohort 1 including 133 patients) and at ICU admission (cohort 2 including 16 patients). Twenty-six patients suffered from thrombosis during their hospital stay: 19 patients in cohort 1 and 7 patients in cohort 2. The neural net predicts COVID-19 related thrombosis based on C-reactive protein (relative importance 14%), sex (10%), thrombin generation (TG) time-to-tail (10%), α
2
-Macroglobulin (9%), TG curve width (9%), thrombin-α
2
-Macroglobulin complexes (9%), plasmin generation lag time (8%), serum IgM (8%), TG lag time (7%), TG time-to-peak (7%), thrombin-antithrombin complexes (5%), and age (5%). This neural net can predict COVID-19-thrombosis at the time of hospital admission with a positive predictive value of 98%-100%.
Purpose
To systematically review and meta-analyse published data on the diagnostic performance of
18
F-FDG PET/CT in detecting bone marrow involvement in patients with newly diagnosed diffuse large ...B-cell lymphoma (DLBCL).
Methods
PubMed/MEDLINE and Embase were systematically searched for relevant studies. The methodological quality of each study was assessed. Sensitivities and specificities of FDG PET/CT in individual studies were calculated and meta-analysed with a random effects model. A summary receiver operating characteristic curve (sROC) was constructed with the Moses-Shapiro-Littenberg method. Weighted summary proportions of discrepancies between the FDG PET/CT and (blind) bone marrow biopsy (BMB) results among all patients were calculated.
Results
Seven studies, with a total of 654 patients with newly diagnosed DLBCL, were included. Overall, the quality of the included studies was moderate. The sensitivity and specificity of FDG PET/CT for detecting bone marrow involvement ranged from 70.8 % to 95.8 % and from 99.0 % to 100 %, with pooled estimates of 88.7 % (95 % confidence interval, CI, 82.5 – 93.3 %) and 99.8 % (95 % CI 98.8 – 100 %), respectively. The area under the sROC curve was 0.9983. The weighted summary proportion of FDG PET/CT-negative patients with positive BMB findings among all patients was 3.1 % (95 % CI 1.8 – 5.0 %) and the weighted summary proportion of FDG PET/CT-positive patients with negative BMB findings among all patients was 12.5 % (95 % CI 8.4 – 17.3 %).
Conclusion
FDG PET/CT is accurate and complementary to BMB for detecting bone marrow involvement in patients with newly diagnosed DLBCL. A negative FDG PET/CT scan cannot rule out the presence of bone marrow involvement, but positive FDG PET/CT findings obviate the need for BMB for the detection of bone marrow involvement in these patients.
BACKGROUND—Von Willebrand factor (VWF) multimer size is controlled through continuous proteolysis by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type I motif, member 13). This ...prevents spontaneous platelet agglutination and microvascular obstructions. ADAMTS13 deficiency is associated with thrombotic thrombocytopenic purpura, in which life-threatening episodes of microangiopathy damage kidneys, heart, and brain. Enigmatically, a complete ADAMTS13 deficiency does not lead to continuous microangiopathy. We hypothesized that plasmin, the key enzyme of the fibrinolytic system, serves as a physiological backup enzyme for ADAMTS13 in the degradation of pathological platelet–VWF complexes.
METHODS AND RESULTS—Using real-time microscopy, we determined that plasmin rapidly degrades platelet–VWF complexes on endothelial cells in absence of ADAMTS13, after activation by urokinase-type plasminogen activator or the thrombolytic agent streptokinase. Similarly, plasmin degrades platelet–VWF complexes in platelet agglutination studies. Plasminogen directly binds to VWF and its A1 domain in a lysine-dependent manner, as determined by enzyme-linked immunosorbent assay. Plasma levels of plasmin–α2-antiplasmin complexes increase with the extent of thrombocytopenia in patients with acute episodes of thrombotic thrombocytopenic purpura, independent of ADAMTS13 activity. This indicates that plasminogen activation takes place during microangiopathy. Finally, we show that the thrombolytic agent streptokinase has therapeutic value for Adamts13 mice in a model of thrombotic thrombocytopenic purpura.
CONCLUSIONS—We propose that plasminogen activation on endothelial cells acts as a natural backup for ADAMTS13 to degrade obstructive platelet–VWF complexes. Our findings indicate that thrombolytic agents may have therapeutic value in the treatment of microangiopathies and may be useful to bypass inhibitory antibodies against ADAMTS13 that cause thrombotic thrombocytopenic purpura.
The majority of patients diagnosed with thrombotic thrombocytopenic purpura have autoantibodies directed towards the spacer domain of ADAMTS13.
In this study we explored the epitope specificity and ...immunoglobulin class and immunoglobulin G subclass distribution of anti-ADAMTS13 antibodies. The epitope specificity of anti-spacer domain antibodies was examined using plasma from 48 patients with acute acquired thrombotic thrombocytopenic purpura by means of immunoprecipitation of ADAMTS13 variants containing single or multiple alanine substitutions. Using similar methods, we also determined the presence of anti-TSP2-8 and CUB1-2 domain antibodies in this cohort of patients.
Antibody profiling revealed that anti-ADAMTS13 immunoglobulin G1 and immunoglobulin G4 predominate in plasma of patients with acquired thrombotic thrombocytopenic purpura. Analysis of anti-spacer domain antibodies revealed that Arg568 and Phe592, in addition to residues Arg660, Tyr661, and Tyr665, also contribute to an antigenic surface in the spacer domain. The majority of patients (90%) lost reactivity towards the spacer domain following introduction of multiple alanine substitutions at Arg568, Phe592, Arg660, Tyr661 and Tyr665. Anti-TSP2-8 and anti-CUB1-2 domain-directed antibodies were present in, respectively, 17% and 35% of the patients' samples analyzed.
Immunoglobulin G directed towards a single antigenic surface comprising residues Arg568, Phe592, Arg660, Tyr661 and Tyr665 predominates in the plasma of patients with acquired thrombotic thrombocytopenic purpura.
In the majority of patients with acquired thrombotic thrombocytopenic purpura (TTP), antibodies are directed toward the spacer domain of ADAMTS13. We have previously shown that region Y658-Y665 is ...involved. We now show that replacement of R660, Y661, or Y665 with alanine in ADAMTS13 reduced/abolished the binding of 2 previously isolated human monoclonal antibodies and polyclonal antibodies derived from plasma of 6 patients with acquired TTP. We investigated whether these residues also influenced cleavage of short von Willebrand factor (VWF) fragment substrate VWF115. An ADAMTS13 variant (R660A/Y661A/Y665A, ADAMTS13-RYY) showed a 12-fold reduced catalytic efficiency (kcat/Km) arising from greatly reduced (> 25-fold) binding, demonstrated by surface plasmon resonance. The influence of these residue changes on full-length VWF was determined with denaturing and flow assays. ADAMTS13-RYY had reduced activity in both, with proteolysis of VWF unaffected by autoantibody. Binding of ADAMTS13-RYY mutant to VWF was, however, similar to normal. Our results demonstrate that residues within Y658-Y665 of the ADAMTS13 spacer domain that are targeted by autoantibodies in TTP directly interact with a complementary exosite (E1660-R1668) within the VWF A2 domain. Residues R660, Y661, and Y665 are critical for proteolysis of short VWF substrates, but wider domain interactions also make important contributions to cleavage of full-length VWF.
Recently, we showed that ADAMTS13 circulates in an open conformation during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP). Although the cause of this conformational ...change remains elusive, ADAMTS13 is primarily closed in iTTP patients in remission with ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, as well as after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, immunoglobulin G from 18 acute iTTP patients was purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14 of 18 (78%) samples, proving that anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n = 197) that also included plasma samples from iTTP patients in remission in whom ADAMTS13 activity was <50%. The open ADAMTS13 conformation was found during acute iTTP, as well as in patients in remission with ADAMTS13 activity <50% and in half of the patients with ADAMTS13 activity >50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus, open ADAMTS13 is a hallmark of acute iTTP, as well as a novel biomarker that can be used to detect subclinical iTTP in patients in remission. Finally, a long-term follow-up study in 1 iTTP patient showed that the open conformation precedes a substantial drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management.
•Anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation.•An open ADAMTS13 conformation is a novel and sensitive biomarker for subclinical iTTP.
Display omitted
Background
To assess the performance of whole‐body MRI including diffusion‐weighted imaging (whole‐body MRI‐DWI) for the detection of residual disease after completion of treatment in lymphoma ...patients.
Methods
Twenty‐six patients with lymphoma prospectively underwent whole‐body MRI‐DWI (1.5 Tesla MR) and 18F‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography (FDG‐PET)/computed tomography (CT) for posttreatment evaluation which were visually assessed. Apparent diffusion coefficient (ADC) and FDG‐PET/CT standardized uptake value measurements were performed in all residual lesions. An unblinded expert panel reviewed all cases and determined the presence or absence of posttreatment residual disease using all available imaging (except for whole‐body MRI‐DWI), clinical, and histopathological information with a follow‐up of at least 6 months. The performance of whole‐body MRI‐DWI was compared with this panel reference standard.
Results
Five of 26 patients were diagnosed with residual disease. Sensitivity and specificity for detection of residual disease with whole‐body MRI‐DWI were 100% and 62%, respectively. By ROC analysis, the optimal threshold of ADC was 1.21 × 10−3 mm2/s with sensitivity and specificity of 100% and 91.7%, respectively.
Conclusion
Our initial results suggest that visual whole‐body MRI‐DWI analysis has a very good sensitivity for detecting viable residual lesions after completion of therapy but lacks specificity. ADC measurements could potentially increase the specificity of whole‐body MRI. J. MAGN. RESON. IMAGING 2015;42:1646–1655.
Purpose
This study aimed to determine the prognostic value of whole‐body maximum standardized uptake value (SUVmax), whole‐body metabolic tumor volume (MTV), and whole‐body total lesion glycolysis ...(TLG) at pretreatment 18F‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography/computed tomography (FDG‐PET/CT) in patients with newly diagnosed diffuse large B‐cell lymphoma (DLBCL).
Materials and Methods
Seventy‐three patients with newly diagnosed DLBCL who had undergone FDG‐PET/CT before rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (R‐CHOP) immunochemotherapy were retrospectively included. All FDG‐avid lesions in each patient were segmented using semi‐automated software to calculate whole‐body SUVmax, whole‐body MTV, and whole‐body TLG values. Cox regression analyses were used to determine the associations of whole‐body SUVmax, whole‐body MTV, whole‐body TLG, and dichotomized National Comprehensive Cancer Network International Prognostic Index (NCCN‐IPI) risk group (low risk vs. high risk) with progression‐free survival (PFS) and overall survival (OS).
Results
On univariate Cox regression analysis, only the NCCN‐IPI was a significant predictor of PFS (P = 0.024), and only the NCCN‐IPI and whole‐body MTV were significant predictors of OS (P = 0.039 and P = 0.043, respectively). In the multivariate Cox proportional hazards model, only the NCCN‐IPI remained an independent predictive factor of PFS (P = 0.024) and OS (P = 0.039).
Conclusion
Whole‐body SUVmax, whole‐body MTV, and whole‐body TLG do not provide any prognostic information in DLBCL beyond that which can already be obtained by the NCCN‐IPI. Therefore, the NCCN‐IPI remains the most important prognostic tool in this disease.
PDF
