Thrombotic thrombocytopenic purpura LÄMMLE, B.; KREMER HOVINGA, J. A.; ALBERIO, L.
Journal of thrombosis and haemostasis,
August 2005, Letnik:
3, Številka:
8
Journal Article
Recenzirano
Odprti dostop
This overview summarizes the history of thrombotic thrombocytopenic purpura (TTP) from its initial recognition in 1924 as a most often fatal disease to the discovery in 1997 of ADAMTS‐13 deficiency ...as a major risk factor for acute disease manifestation. The cloning of the metalloprotease, ADAMTS‐13, an essential regulator of the extremely adhesive unusually large von Willebrand factor (VWF) multimers secreted by endothelial cells, as well as ADAMTS‐13 structure and function are reviewed. The complex, initially devised assays for ADAMTS‐13 activity and the possible limitations of static in vitro assays are described. A new, simple assay using a recombinant 73‐amino acid VWF peptide as substrate will hopefully be useful. Hereditary TTP caused by homozygous or double heterozygous ADAMTS‐13 mutations and the nature of the mutations so far identified are discussed. Recognition of this condition by clinicians is of utmost importance, because it can be easily treated and – if untreated – frequently results in death. Acquired TTP is often but not always associated with severe, autoantibody‐mediated ADAMTS‐13 deficiency. The pathogenesis of cases without severe deficiency of the VWF‐cleaving protease remains unknown, affected patients cannot be distinguished clinically from those with severely decreased ADAMTS‐13 activity. Survivors of acute TTP, especially those with autoantibody‐induced ADAMTS‐13 deficiency, are at a high risk for relapse, as are patients with hereditary TTP. Patients with thrombotic microangiopathies (TMA) associated with hematopoietic stem cell transplantation, neo‐plasia and several drugs, usually have normal or only moderately reduced ADAMTS‐13 activity, with the exception of ticlopidine‐induced TMA. Diarrhea‐positive‐hemolytic uremic syndrome (D+ HUS), mainly occurring in children is due to enterohemorrhagic Escherichia coli infection, and cases with atypical, D− HUS may be associated with factor H abnormalities. Treatment of acquired idiopathic TTP involves plasma exchange with fresh frozen plasma (FFP), and probably immunosuppression with corticosteroids is indicated. We believe that, at present, patients without severe acquired ADAMTS‐13 deficiency should be treated with plasma exchange as well, until better strategies become available. Constitutional TTP can be treated by simple FFP infusion that rapidly reverses acute disease and – given prophylactically every 2–3 weeks – prevents relapses. There remains a large research agenda to improve diagnosis of TMA, gain further insight into the pathophysiology of the various TMA and to improve and possibly tailor the management of affected patients.
The apparently spontaneous development of autoantibodies to ADAMTS13 in previously healthy individuals is a major cause of thrombotic thrombocytopenic purpura (TTP). Epitope mapping studies have ...shown that in most patients antibodies directed towards the spacer domain of ADAMTS13 are present. A single antigenic surface comprising Arg660, Tyr661 and Tyr665 that contributes to the productive binding of ADAMTS13 to unfolded von Willebrand factor is targeted by anti‐spacer domain antibodies. Antibodies directed to the carboxyl‐terminal CUB1–2 and TSP2–8 domains have also been observed in the plasma of patients with acquired TTP. As yet it has not been established whether this class of antibodies modulates ADAMTS13 activity. Inspection of the primary sequence of human monoclonal anti‐ADAMTS13 antibodies suggests that the variable heavy chain germline gene segment VH1–69 is frequently incorporated. We suggest a model in which ‘shape complementarity’ between the spacer domain and residues encoded by the VH1–69 gene segment explain the preferential use of this variable heavy chain gene segment. Finally, a model is presented for the development of anti‐ADAMTS13 antibodies in previously healthy individuals that incorporates the recent identification of HLA DRB1*11 as a risk factor for acquired TTP.
Background: Autoantibodies directed towards ADAMTS13 are present in the majority of patients with acquired thrombotic thrombocytopenic purpura (TTP). Analysis of a set of antibodies derived from two ...patients with acquired TTP revealed frequent use of the VH1‐69 heavy chain gene segment for the assembly of anti‐ADAMTS13 antibodies. Objective: We explored the ability of two VH1‐69 germline gene‐encoded antibodies to inhibit the von Willebrand factor (VWF)‐processing activity of ADAMTS13 under different experimental conditions. Furthermore, the presence of VH1‐69 encoded anti‐ADAMTS13 antibodies in 40 patients with acquired TTP was monitored using monoclonal antibody G8, which specifically reacts with an idiotype expressed on VH1‐69 encoded antibodies. Methods and Results: Binding of the two VH1‐69 encoded monoclonal antibodies was dependent on the presence of the spacer domain. Both antibodies inhibited ADAMTS13 activity under static conditions, as measured by cleavage of FRETS‐VWF73 substrate and cleavage of VWF multimers. The recombinant antibodies were also capable of inhibiting the processing of UL‐VWF strings on the surface of endothelial cells. G8‐reactive antibodies directed towards ADAMTS13 were present in plasma of all patients containing anti ADAMTS13 antibodies. Conclusions: These results suggest that VH1‐69 derived antibodies directed towards ADAMTS13 develop in the majority of patients with acquired TTP.
Essential thrombocythemia is a chronic myeloproliferative neoplasm. It is extremely rare in children below 15 years of age with an estimated annual incidence of only 0.09 per million. Usually, ...clinical symptoms associated with essential thrombocythemia are mild or absent.
Here, we present the case of a 14-year-old female patient fulminantly presenting with acute symptoms comprising visual impairment, palmar and plantar stabbing pain. Blood count revealed massive thrombocytosis of 2373 × 10
/L. Bone marrow morphology showed elevated numbers of mature megakaryocytes. Von Willebrand factor activity/antigen ratio was significantly reduced compatible with an acquired Von Willebrand syndrome associated with high platelet counts. Molecular analyses for driver mutations of myeloproliferative neoplasms including
,
were negative. Acute therapy comprising hyperhydration and oxygen supply complemented by acetylsalicylic acid led to amelioration of symptoms. Medication with hydroxycarbamide maintained a significant reduction of platelet counts but had to be reduced or withheld several times due to neutropenia. Repeated bleeding episodes observed in the course were clearly associated with increases in platelet counts above 1200 × 10
/L explained by acquired von Willebrand syndrome. Sixteen months after diagnosis, therapy was switched to pegylated interferon and platelet counts could be stabilized without significant side effects.
Background: Over the last 4 years ADAMTS‐13 measurement underwent dramatic progress with newer and simpler methods. Aims: Blind evaluation of newer methods for their performance characteristics. ...Design: The literature was searched for new methods and the authors invited to join the evaluation. Participants were provided with a set of 60 coded frozen plasmas that were prepared centrally by dilutions of one ADAMTS‐13‐deficient plasma (arbitrarily set at 0%) into one normal‐pooled plasma (set at 100%). There were six different test plasmas ranging from 100% to 0%. Each plasma was tested ‘blind’ 10 times by each method and results expressed as percentage vs. the local and the common standard provided by the organizer. Results: There were eight functional and three antigen assays. Linearity of observed‐vs.‐expected ADAMTS‐13 levels assessed as r2 ranged from 0.931 to 0.998. Between‐run reproducibility expressed as the (mean) CV for repeated measurements was below 10% for three methods, 10–15% for five methods and up to 20% for the remaining three. F‐values (analysis of variance) calculated to assess the capacity to distinguish between ADAMTS‐13 levels (the higher the F‐value, the better the capacity) ranged from 3965 to 137. Between‐method variability (CV) amounted to 24.8% when calculated vs. the local and to 20.5% when calculated vs. the common standard. Comparative analysis showed that functional assays employing modified von Willebrand factor peptides as substrate for ADAMTS‐13 offer the best performance characteristics. Conclusions: New assays for ADAMTS‐13 have the potential to make the investigation/management of patients with thrombotic microangiopathies much easier than in the past.
We report on our patient (case 2) who experienced a first acute episode of thrombotic thrombocytopenic purpura (TTP) at the age of 19 years during her first pregnancy in 1976 which ended in a ...spontaneous abortion in the 30th gestational week. Treatment with red blood cell concentrates was implemented and splenectomy was performed. After having suffered from several TTP episodes in 1977, possibly mitigated by acetylsalicylic acid therapy, an interruption and sterilization were performed in 1980 in her second pregnancy thereby avoiding another disease flare-up. Her elder sister (case 1) had been diagnosed with TTP in 1974, also during her first pregnancy. She died in 1977 during her second pregnancy from a second acute TTP episode.
In 2013 a severe ADAMTS13 deficiency of <10% without detectable ADAMTS13 inhibitor was repeatedly found. Investigation of the ADAMTS13 gene showed that the severe ADAMTS13 deficiency was caused by compound heterozygous ADAMTS13 mutations: a premature stop codon in exon 2 (p.Q44X), and a missense mutation in exon 24 (p.R1060W) associated with low but measurable ADAMTS13 activity.
Genetic analysis of the ADAMTS13 gene is important in TTP patients of all ages if an ADAMTS13 inhibitor has been excluded.
Background and purpose
Cerebral venous sinus thrombosis (CVST) has been described after vaccination against SARS‐CoV‐2. The clinical characteristics of 213 post‐vaccination CVST cases notified to the ...European Medicines Agency are reported.
Methods
Data on adverse drug reactions after SARS‐CoV‐2 vaccination notified until 8 April 2021 under the Medical Dictionary for Regulatory Activities Term ‘Central nervous system vascular disorders’ were obtained from the EudraVigilance database. Post‐vaccination CVST was compared with 100 European patients with CVST from before the COVID‐19 pandemic derived from the International CVST Consortium.
Results
In all, 213 CVST cases were identified: 187 after AstraZeneca/Oxford (ChAdOx1 nCov‐19) vaccination and 26 after a messenger RNA (mRNA) vaccination (25 with Pfizer/BioNTech, BNT162b2, and one with Moderna, mRNA‐1273). Thrombocytopenia was reported in 107/187 CVST cases (57%, 95% confidence interval CI 50%–64%) in the ChAdOx1 nCov‐19 group, in none in the mRNA vaccine group (0%, 95% CI 0%–13%) and in 7/100 (7%, 95% CI 3%–14%) in the pre‐COVID‐19 group. In the ChAdOx1 nCov‐19 group, 39 (21%) reported COVID‐19 polymerase chain reaction tests were performed within 30 days of CVST symptom onset, and all were negative. Of the 117 patients with a reported outcome in the ChAdOx1 nCov‐19 group, 44 (38%, 95% CI 29%–47%) had died, compared to 2/10 (20%, 95% CI 6%–51%) in the mRNA vaccine group and 3/100 (3%, 95% CI 1%–8%) in the pre‐COVID‐19 group. Mortality amongst patients with thrombocytopenia in the ChAdOx1 nCov‐19 group was 49% (95% CI 39%–60%).
Conclusions
Cerebral venous sinus thrombosis occurring after ChAdOx1 nCov‐19 vaccination has a clinical profile distinct from CVST unrelated to vaccination. Only CVST after ChAdOx1 nCov‐19 vaccination was associated with thrombocytopenia.
We used the EudraVigilance database of the European Medicines Agency to identify 213 CVST cases after COVID‐19 vaccination ‐ 187 after AstraZeneca/Oxford (ChAdOx1 nCov‐19) vaccination and 26 after a mRNA vaccination (25 with Pfizer/BioNTech BNT162b2 and one with Moderna mRNA‐1273). Only CVST after vaccination with ChAdOx1 nCov‐19 was associated with thrombocytopenia. We compared post‐vaccination CVST to 100 European patients with CVST from before the COVID‐19 pandemic and showed that CVST occurring after ChAdOx1 nCov‐19 vaccination has a clinical profile distinct from CVST unrelated to vaccination.
Background and purpose
High mortality rates have been reported in patients with cerebral venous sinus thrombosis (CVST) due to vaccine‐induced immune thrombotic thrombocytopenia (VITT) after ...vaccination with adenoviral vector SARS‐CoV‐2 vaccines. The aim of this study was to evaluate whether the mortality of patients with CVST‐VITT has decreased over time.
Methods
The EudraVigilance database of the European Medicines Agency was used to identify cases of CVST with concomitant thrombocytopenia occurring within 28 days of SARS‐CoV‐2 vaccination. Vaccines were grouped based on vaccine type (adenoviral or mRNA). Cases with CVST onset until 28 March were compared to cases after 28 March 2021, which was the day when the first scientific paper on VITT was published.
Results
In total, 270 cases of CVST with thrombocytopenia were identified, of which 266 (99%) occurred after adenoviral vector SARS‐CoV‐2 vaccination (ChAdOx1 nCoV‐19, n = 243; Ad26.COV2.S, n = 23). The reported mortality amongst adenoviral cases with onset up to 28 March 2021 was 47/99 (47%, 95% confidence interval 37%–58%) compared to 36/167 (22%, 95% confidence interval 16%–29%) in cases with onset after 28 March (p < 0.001). None of the four cases of CVST with thrombocytopenia occurring after mRNA vaccination died.
Conclusion
The reported mortality of CVST with thrombocytopenia after vaccination with adenoviral vector‐based SARS‐CoV‐2 vaccines has significantly decreased over time, which may indicate a beneficial effect of earlier recognition and/or improved treatment on outcome after VITT.
The EudraVigilance database of the European Medicines Agency was used to identify cases of cerebral venous sinus thrombosis (CVST) with concomitant thrombocytopenia occurring within 28 days of SARS‐CoV‐2 vaccination. The reported mortality of CVST with thrombocytopenia after vaccination with adenoviral vector‐based vaccines significantly decreased over time with a mortality rate of 47% (95% confidence interval 37%–58%) in cases with CVST onset prior to 28 March 2021 compared to 22% (95% confidence interval 16%–29%) in cases after 28 March (p < 0.001). This declining mortality may indicate a beneficial effect of earlier recognition and/or improved treatment on outcome after vaccine‐induced thrombotic thrombocytopenia.
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