118 research outputs found
Active von Willebrand factor in thrombotic thrombocytopenic purpura and malaria
No full textThrombotic thrombocytopenic purpura (TTP) and malaria are two diseases of distinct origin. TTP is a rare disorder caused by a deficiency of the von Willebrand factor (VWF) cleaving protease ADAMTS13. Malaria is a poverty-related disease caused by protozoan parasites from the genus Plasmodium. TTP and malaria share several clinical symptoms including intravascular platelet agglutination with thrombocytopenia, haemolytic anemia, neurological symptoms and fever. VWF plays an essential role in the adhesion of platelets to the injured vessel wall under conditions of blood flow. The platelet-binding site of plasma VWF, which is located in the A1 domain, is encrypted to prevent unwanted interaction with platelets. In order to arrest bleeding, VWF is converted from its latent conformation into an active conformation, a conformation in which the platelet-binding site in the A1 domain is exposed. Persistence of active VWF in the circulation would cause undesired VWF-platelet aggregate formation, resulting in thrombosis and/or bleeding from thrombocytopenia. Therefore, tight regulation of VWF activation and inactivation mechanisms is essential to prevent the occurrence of both bleeding and thrombotic events. An important regulator of VWF activity is ADAMTS13, a metalloprotease that cleaves VWF. TTP is caused by a genetic or auto-immune based deficiency or dysfunction of ADAMTS13. Aberrations in VWF have been described for both TTP and malaria. In acute TTP, when patients suffer from thrombosis and require plasma exchange, absence of ADAMTS13 results in the presence of active VWF multimers in the circulation. Consequently, microthrombi are being formed that cause occlusion of the microvasculature and organ damage. With respect to remission, when patients do not longer require plasma exchange to prevent thrombosis, no information is available about active VWF. For malaria, elevated VWF-antigen levels have been reported in field studies, but the eventual role of active VWF in the development of platelet-clumping and thrombocytopenia is unknown. This thesis aims to provide more insight into the origin of active VWF and the role of active VWF in TTP and malaria. Chapter 3 focuses on endothelial cells and reports studies on the origin of active VWF. Chapter 4 describes VWF- and ADAMTS13-related features in a cohort of TTP patients in remission and gives insight in the composition of active VWF multimers. Chapter 5 addresses the relevance of an ADAMTS13 activity assay, based on fluorescence resonance energy transfer, with regard to TTP diagnosis. Chapters 6 and 7 describe the relation between (active) VWF, ADAMTS13 and thrombocytopenia in an experimental human infection malaria study involving healthy volunteers (chapter 6) and in a field study on the Indonesian island Sumba (chapter 7). In the last chapter (chapter 8), the findings from the preceding chapters are taken together and discussed
Fatal cerebral hemorrhage in a patient with thrombotic thrombocytopenic purpura with a normal platelet count during treatment with caplacizumab
No full textAcquired 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
Acquired TTP: ADAMTS13 meets the immune system
No full textThe 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 TT
Elastase Mediated Fibrinolysis in Acute Promyelocytic Leukemia
No full textSummaryThe bleeding syndrome of acute promyelocytic leukemia (APL) is complex and consists of disseminated intravascular coagulation (DIC) and hyperfibrinolysis. Elastase, derived from malignant promyelocytes, is believed to mediate the fibrinogeno- and fibrinolysis by aspecific proteolysis. In this study we measured the role of elastase in fifteen patients with APL by using an assay for elastase degraded fibrin(ogen) and the results were compared with those obtained in patients with sepsis induced DIC.High levels of elastase were observed in sepsis and APL. The levels of fibrinogen and fibrin degradation products were significantly higher in APL patients compared to patients with sepsis induced DIC. Nevertheless, the level of elastase degraded fibrin(ogen) was higher in the sepsis group (635.3 ng/ml, compared to 144.3 ng/ml in APL; p <0.0001). So, the enormous increase in fibrin and fibrinogen degradation products in APL cannot be explained by elastase activity. This study suggests a minor role for elastase mediated proteolysis in the hemorrhagic diathesis in APL patients.</jats:p
Open ADAMTS13 conformation index predicts earlier relapse in immune-mediated thrombotic thrombocytopenic purpura.
No full textBACKGROUND
ADAMTS13 adopts an open conformation in immune-mediated thrombotic thrombocytopenic purpura (iTTP) patients in acute phase while being closed in healthy donors. We reported that a substantial number of iTTP patients in remission with restored ADAMTS13 activity (>50%) still had an open ADAMTS13 conformation, although a closed conformation is expected given the extent of remission.
OBJECTIVE
To investigate whether open ADAMTS13, represented by conformation index >0.5, is associated with a risk for earlier ADAMTS13 and/or clinical relapse.
PATIENTS/METHODS
We collected follow-up data (ADAMTS13 parameters, ADAMTS13 and clinical relapse and treatment) from 81 iTTP patients in remission with ADAMTS13 activity above 50%.
RESULTS
During follow-up, 19 ADAMTS13 and 10 clinical relapses were reported (median follow up period: 20 months). First, open or closed ADAMTS13 conformation was dichotomized based on the 0.5 conformation index cut-off. Open ADAMTS13 (conformation index >0.5) was not identified as a risk for ADAMTS13 and clinical relapse (log-rank test and Cox regression model). In contrast, by identifying the optimal conformation index cut-off for relapse prediction, using classification and regression tree analysis, conformation index >0.645 and >0.835 were shown to be a risk for respectively ADAMTS13 relapse (hazard ratio (HR) 3.3, (95% CI:1.3-8.3), p=0.01) and clinical relapse (HR 4.4, (95% CI:1.3-15.3), p=0.02).
CONCLUSION
Patients with open ADAMTS13 with conformation index >0.645 and >0.835, respectively have an over 3- and 4-fold higher risk for earlier ADAMTS13 and clinical relapse. Hence, ADAMTS13 conformation index could be used to complement ADAMTS13 activity monitoring to timely notice ADAMTS13 relapse and prevent clinical relapse
Diagnostic and therapeutic challenges of severe Rh e-specific IgA-mediated autoimmune hemolytic anemia
No full textGeneration of anti-idiotypic antibodies to detect anti-spacer antibody idiotopes in acute thrombotic thrombocytopenic purpura patients
No full textIn autoantibody-mediated autoimmune diseases, autoantibody profiling allows to stratify patients and link autoantibodies with disease severity and outcome. However, in immune-mediated thrombotic thrombocytopenic purpura patients, stratification according to antibody profiles and their clinical relevance has not been fully explored. We aimed at developing a new type of autoantibody profiling assay for immune-mediated thrombotic thrombocytopenic purpura based on the use of anti-idiotypic antibodies. Anti-idiotypic antibodies against 3 anti-spacer autoantibodies were generated in mice and were used to capture the respective anti-spacer idiotopes from 151 acute immune-mediated thrombotic thrombocytopenic purpura plasma samples. We next deciphered these anti-spacer idiotope profiles in immune-mediated thrombotic thrombocytopenic purpura patients and investigated if these limited idiotope profiles could be linked with disease severity. We developed 3 anti-idiotypic antibodies that recognized particular idiotopes in the anti-spacer autoantibodies II-1, TTP73 or I-9, that are involved in ADAMTS13 binding. Thirty-five, 24 and 42% of patients were positive for antibodies with the II-1, TTP73 and I-9 idiotopes, respectively. Stratifying patients according to the corresponding 8 anti-spacer idiotope profiles revealed an until now unknown insight into the anti-spacer II-1, TTP73 and I-9 idiotope profiles in these patients. Finally, these limited idiotope profiles showed no association with disease severity. We successfully developed 3 anti-idiotypic antibodies that allowed us to determine the profiles of the anti-spacer II-1, TTP73 and I-9 idiotopes in immune-mediated thrombotic thrombocytopenic purpura patients. Increasing the number of patients and/or future development of additional anti-idiotypic antibodies against other anti-ADAMTS13 autoantibodies might allow to identify idiotope profiles of clinical, prognostic value
Sufficient and Timely Autologous Stem Cell Harvest After Chemoimmunotherapy with Alemtuzumab In Combination with Bi-Weekly CHOP as First Line Treatment In Systemic Peripheral T-Cell Lymphomas (PTCL): a Feasibility Analysis From the First Randomized Trial In Systemic PTCL (ACT trial)
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