Prevalence of Overweight and Obesity, Its Complications, and Progression in a 10-Year Follow-Up in the Gutenberg Health Study (GHS).

INTRODUCTION: Overweight and obesity lead to numerous complications and their treatment. The associated costs represent a health and sociopolitical burden. Therefore, the development of overweight and obesity is of great importance for health policy. METHODS: The Gutenberg Health Study (GHS), a population-based observational study of individuals aged 35-74 years in the city of Mainz and the district of Mainz-Bingen, examined current data on the prevalence and development of overweight and obesity and their association with concomitant diseases and medication use. RESULTS: Among men, 48.1% were overweight and 26.3% had obesity. Among women, these proportions were 32.1% and 24.1%, respectively. Elevated body mass index (BMI) was associated with numerous complications, particularly insulin resistance and type 2 diabetes, arterial hypertension, elevated triglycerides and low HDL cholesterol, and cardiovascular disease. Accordingly, medications to treat these conditions were used significantly more often in individuals with elevated BMI. During the 10-year observation period, mean weight increased in the population. Both men and women had a moderate but significant increase in BMI compared to men and women of the same age at baseline. Individual weight changes over the 10-year observation period, on the other hand, were age-dependent. In the two younger age decades, weight gain was observed, while in the oldest age decade, mean body weight decreased. CONCLUSION: These current data confirm that overweight and obesity are associated with relevant complications and that these complications lead to significant use of appropriate medications. The study also suggests that there is a significant trend toward increased prevalence of obesity (BMI ≥30) over the 10-year period.

Open ADAMTS-13 conformation index predicts earlier relapse in immune-mediated thrombotic thrombocytopenic purpura.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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%. RESULTS: 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. CONCLUSION: 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.

A novel von Willebrand factor multimer ratio as marker of disease activity in thrombotic thrombocytopenic purpura.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP), an autoantibody-mediated severe ADAMTS13 deficiency, is caused by insufficient proteolytic processing of von Willebrand factor (VWF) multimers (MMs) and microvascular thrombi. Recurrence of acute iTTP is associated with persistence or reappearance of ADAMTS13 deficiency. Some patients remain in remission despite recurring or persisting severe ADAMTS13 deficiency. In a prospective 2-year observational study, we investigated VWF MM patterns and ADAMTS13 in patients with iTTP in remission and at acute episodes. Of the 83 patients with iTTP, 16 suffered 22 acute episodes whereas 67 remained in clinical remission during follow-up, including 13 with ADAMTS13 <10% and 54 with ADAMTS13 ≥10%. High -molecular weight to low-molecular weight VWF MM ratio based on sodium dodecyl sulfate-agarose gel electrophoresis was compared with ADAMTS13 activity. VWF MM ratio was significantly higher in patients in remission with <10% compared with ≥10% ADAMTS13 activity. Fourteen samples obtained from 13 to 50 days (interquartile range; median, 39) before acute iTTP onset (ADAMTS13 <10% in 9 patients and 10%-26% in 5) showed VWF MM ratios significantly higher than those from 13 patients remaining in remission with ADAMTS13 <10%. At acute iTTP onset, VWF MM ratio decreased significantly and was low in all patients despite <10% ADAMTS13. The VWF MM ratio does not depend exclusively on ADAMTS13 activity. The disappearance of high molecular weight VWF MMs resulting in low VWF MM ratio at iTTP onset may be explained by consumption of larger VWF MMs in the microcirculation. The very high VWF MM ratio preceding acute iTTP recurrence suggests that VWF processing is hampered more than in patients remaining in remission.

One fits all: a highly sensitive combined ddPCR/pyrosequencing system for the quantification of microchimerism after hematopoietic and solid organ transplantation.

OBJECTIVES: A combined digital droplet PCR (ddPCR)/pyrosequencing assay system was developed that demonstrated advantages applicable to multiple qualitative and quantitative molecular genetic diagnostic applications. Data for characterizing this combined approach for hematologic stem cell transplantation (HSCT) and allele quantification from graft-derived cell-free (cf) DNA in solid organ transplantation (SOT) is presented. METHODS: ddPCR and pyrosequencing assays targeting 32 SNPs/markers were established. ddPCR results from 72 gDNAs of 55 patients after allogeneic HSCT and 107 plasma-cfDNAs of 25 liver transplant recipients were compared with established methods/markers, i.e. short-tandem-repeat PCR and ALT, respectively. RESULTS: The ddPCR results were in good agreement with the established marker. The limit of detection was 0.02 % minor allele fraction. The relationship between ddPCR and STR-PCR was linear with R2=0.98 allowing to transfer previously established clinical STR-PCR cut-offs to ddPCR; 50-fold higher sensitivity and a variation coefficient of <2 % enable the use of low DNA concentrations (e.g. pre-sorted cells). ddPCR detected liver allograft injury at least as sensitive as ALT suggesting that ddPCR is a reliable method to monitor the transplant integrity, especially when other biomarkers are lacking (e.g. kidney). CONCLUSIONS: Combining pyrosequencing for genotyping and ddPCR for minor allele quantification enhances sensitivity and precision for the patient after HSCT and SOT. The assay is designed for maximum flexibility. It is expected to be suitable for other applications (sample tracking, prenatal diagnostics, etc.).

COVID-19 as a Potential Trigger for Immune Thrombotic Thrombocytopenic Purpura and Reason for an Unusual Treatment: A Case Report.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare autoimmune disorder characterized by severely reduced activity of the von Willebrand factor (VWF)-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) due to autoantibodies. This leads to the development of pathogenic multimers of VWF, causing a thrombotic microangiopathy with decreased number of platelets, hemolysis, and life-threatening tissue ischemia of mostly brain, heart, and kidneys. Standard treatment of iTTP involves daily plasma exchange to remove ultra large multimers of VWF, inhibitors, substituting ADAMTS13, and the accompaniment of an immunosuppressive treatment with steroids. Recently, caplacizumab was approved for iTTP. Caplacizumab is a nanobody binding the A1 domain of VWF, blocking its interaction with glycoprotein Ib-IX-V platelet receptor and therefore preventing platelet aggregation. VWF activities may serve as therapeutic drug monitoring of caplacizumab, whereas ADAMTS13 activities may be used for biomarkers to guide caplacizumab treatment modalities and overall treatment duration. Additional immunosuppressive treatment by inhibiting autoantibody formation (e.g., the use of Rituximab, a chimeric monoclonal antibody directed against the B-cell antigen CD20) is a further treatment option. Infections are well-known causes for an acute episode for patients with iTTP. The novel SARS-CoV-2 virus is mainly associated with acute respiratory distress as well as diffuse endothelial inflammation and increased coagulopathy. However, little is known about an infection with SARS-CoV-2 virus triggering iTTP relapses. We herein report the case of an acute iTTP episode accompanying a SARS-CoV-2 infection.

Anti-ADAMTS13 autoantibody profiling in patients with immune-mediated thrombotic thrombocytopenic purpura.

Anti-A Disintegrin and Metalloproteinase with a ThromboSpondin type 1 motif, member 13 (ADAMTS13) autoantibodies cause a severe ADAMTS13 deficiency in immune-mediated thrombotic thrombocytopenic purpura (iTTP). ADAMTS13 consists of a metalloprotease (M), a disintegrin-like (D) domain, 8 thrombospondin type 1 repeats (T1-T8), a cysteine-rich (C), a spacer (S), and 2 CUB domains (CUB1-2). We recently developed a high-throughput epitope mapping assay based on small, nonoverlapping ADAMTS13 fragments (M, DT, CS, T2-T5, T6-T8, CUB1-2). With this assay, we performed a comprehensive epitope mapping using 131 acute-phase samples and for the first time a large group of remission samples (n = 50). Next, samples were stratified according to their immunoprofiles, a field that is largely unexplored in iTTP. Three dominant immunoprofiles were found in acute-phase samples: profile 1: only anti-CS autoantibodies (26.7%); profile 2: both anti-CS and anti-CUB1-2 autoantibodies (12.2%); and profile 3: anti-DT, anti-CS, anti-T2-T5, anti-T6-T8, and anti-CUB1-2 autoantibodies (8.4%). Interestingly, profile 1 was the only dominant immunoprofile in remission samples (52.0%). Clinical data were available for a relatively small number of patients with acute iTTP (>68), and no correlation was found between immunoprofiles and disease severity. Nevertheless, profile 1 was linked with younger and anti-T2-T5 autoantibodies with older age and the absence of anti-CUB1-2 autoantibodies with cerebral involvement. In conclusion, identifying acute phase and remission immunoprofiles in iTTP revealed that anti-CS autoantibodies seem to persist or reappear during remission providing further support for the clinical development of a targeted anti-CS autoantibody therapy. A large cohort study with acute iTTP samples will validate possible links between immunoprofiles or anti-domain autoantibodies and clinical data.

Distribution of HOMA-IR in a population-based cohort and proposal for reference intervals.

OBJECTIVES: Insulin resistance (IR) is a hallmark of type 2 diabetes mellitus (DM). The homeostatic model assessment of insulin resistance (HOMA-IR) provides an estimate for IR from fasting glucose and insulin serum concentrations. The aim of this study was to obtain a reference interval for HOMA-IR for a specific insulin immunoassay. METHODS: The Gutenberg Health Study (GHS) is a population-based, prospective, single-center cohort study in Germany with 15,030 participants aged 35-74 years. Fasting glucose, insulin, and C-peptide were available in 10,340 participants. HOMA-IR was calculated in this group and three reference subgroups with increasingly more stringent inclusion criteria. Age- and sex-dependent distributions of HOMA-IR and reference intervals were obtained. In a substudy three insulin assays were compared and HOMA-IR estimated for each assay. RESULTS: Among the 10,340 participants analyzed there were 6,590 non-diabetic, 2,901 prediabetic, and 849 diabetic individuals. Median (interquartile range [IQR]) HOMA-IR was 1.54 (1.13/2.19), 2.00 (1.39/2.99), and 4.00 (2.52/6.51), respectively. The most stringently selected reference group consisted of 1,065 persons. Median (IQR) HOMA-IR was 1.09 (0.85/1.42) with no significant difference between men and women. The 97.5th percentile was 2.35. There was a non-significant trend towards higher values with older age. Comparison of three immunoassays for insulin showed an unsatisfactory correlation among the assays and systematic differences in calculated HOMA-IR. CONCLUSIONS: We present HOMA-IR reference intervals for adults derived by more or less stringent selection criteria for the reference cohort. In addition we show that assay specific reference intervals for HOMA-IR are required.

Pathogenic lipid-binding antiphospholipid antibodies are associated with severity of COVID-19.

BACKGROUND: Coronavirus disease 19 (COVID-19)-associated coagulopathy is a hallmark of disease severity and poor prognosis. The key manifestations of this prothrombotic syndrome-microvascular thrombosis, stroke, and venous and pulmonary clots-are also observed in severe and catastrophic antiphospholipid syndrome. Antiphospholipid antibodies (aPL) are detectable in COVID-19 patients, but their association with the clinical course of COVID-19 remains unproven. OBJECTIVES: To analyze the presence and relevance of lipid-binding aPL in hospitalized COVID-19 patients. METHODS: Two cohorts of 53 and 121 patients from a single center hospitalized for PCR-proven severe acute respiratory syndrome-coronavirus 2 infection were analyzed for the presence of aPL and clinical severity of COVID-19. RESULTS: We here demonstrate that lipid-binding aPL are common in COVID-19. COVID-19 patients with lipid-binding aPL have higher median concentrations of C-reactive protein and D-dimer, and are more likely to have a critical clinical course and fatal outcome. Lipid-binding aPL isolated from COVID-19 patients target the recently described cell surface complex of lysobisphosphatidic acid (LBPA) with the protein C receptor (EPCR) to induce prothrombotic and inflammatory responses in monocytes and endothelial cells. We show that B1a cells producing lipid-reactive aPL of the IgG isotype circulate in the blood of COVID-19 patients. In vivo, COVID-19 aPL accelerate thrombus formation in an experimental mouse model dependent on the recently delineated signaling pathway involving EPCR-LBPA. CONCLUSIONS: COVID-19 patients rapidly expand B1a cells secreting pathogenic lipid-binding aPL with broad thrombotic and inflammatory effects. The association with markers of inflammation and coagulation, clinical severity, and mortality suggests a causal role of aPL in COVID-19-associated coagulopathy.

Diagnosis of Hereditary TTP Caused by Homozygosity for a Rare Complex ADAMTS13 Allele After Salmonella Infection in a 43-Year-Old Asylum Seeker.

A 43-year-old Armenian patient was diagnosed with salmonella infection and thrombotic microangiopathy (TMA). The clinical course was benign with resolution of all laboratory alterations after antibiotic treatment. Constantly deficient ADAMTS13 activity without ADAMTS13 inhibitors and evidence of homozygosity for a rare complex ADAMTS13 allele led to the diagnosis of congenital thrombotic thrombocytopenic purpura (cTTP). Half-life of ADAMTS13 after plasma infusion was calculated (27,6h) and double blinded plasma infusion as well as ergometric exercise with and without prior plasma infusion undertaken to investigate suspected smoldering TTP activity.

No Evidence for Classic Thrombotic Microangiopathy in COVID-19.

BACKGROUND: Coronavirus disease-2019 (COVID-19) triggers systemic infection with involvement of the respiratory tract. There are some patients developing haemostatic abnormalities during their infection with a considerably increased risk of death. MATERIALS AND METHODS: Patients (n = 85) with SARS-CoV-2 infection attending the University Medical Center, Mainz, from 3 March to 15 May 2020 were retrospectively included in this study. Data regarding demography, clinical features, treatment and laboratory parameters were analyzed. Twenty patients were excluded for assessment of disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) due to lack of laboratory data. RESULTS: COVID-19 patients (n = 65) were investigated, 19 with uncomplicated, 29 with complicated, and 17 with critical course; nine (13.8%) died. Seven patients showed overt DIC according to the ISTH criteria. The fibrinogen levels dropped significantly in these patients, although not below 100 mg/dl. Hallmarks of TMA, such as thrombocytopenia and microangiopathic haemolytic anaemia, were not detected in any of our COVID-19 patients. ADAMTS13 activity was mildly to moderately reduced in 4/22 patients, all having strongly elevated procalcitonin levels. CONCLUSION: DIC occurred in 7/65 COVID-19 patients but fibrinogen and platelet consumption were compensated in almost all. ADAMTS13 assays excluded TTP and hallmarks of classic TMA were absent in all investigated patients. We hypothesize that the lacking erythrocyte fragmentation and only mild platelet consumption in severe COVID-19 are due to a microangiopathy predominantly localized to the alveolar microcirculation with a low blood pressure gradient.

Influence of Personality, Resilience and Life Conditions on Depression and Anxiety in 104 Patients Having Survived Acute Autoimmune Thrombotic Thrombocytopenic Purpura.

Autoimmune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening, relapsing disease in which an acquired deficiency of the enzyme ADAMTS13 leads to generalised microvascular thrombosis. Survivors have a high prevalence of depression and impaired cognitive function. The aim of this study was to determine whether life circumstances and personality have an influence on the development and severity of depression and anxiety in iTTP patients and how they impact the quality of life. With validated questionnaires, we examined the prevalence of depression and anxiety symptoms in 104 iTTP patients, as well as parameters of subjective cognitive deficits, quality of life, attitude to life and resilience. iTTP patients had significantly more depressive symptoms (p < 0.001), a tendency to have anxiety disorders (p = 0.035) and a significantly worse cognitive performance (p = 0.008) compared to the controls. Sex, age, physical activity and partnership status had no significant influence on depression, whereas the number of comorbidities did. Lower scores of resilience, attitude to life and quality of life were reported by patients compared to controls. iTTP patients had a high prevalence of depression and anxiety, as well as a more negative attitude to life and low resilience. Resilience correlated negatively with the severity of the depression. Furthermore, quality of life and cognitive performance were significantly reduced.

Immunogenic hotspots in the spacer domain of ADAMTS13 in immune-mediated thrombotic thrombocytopenic purpura.

BACKGROUND: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by anti-ADAMTS13 autoantibodies inducing a severe deficiency of ADAMTS13. Epitope mapping studies on samples obtained during acute iTTP episodes have shown that the iTTP immune response is polyclonal, with almost all patients having autoantibodies targeting the spacer domain of ADAMTS13. OBJECTIVES: To identify the immunogenic hotspots in the spacer domain of ADAMTS13. PATIENTS/METHODS: A library of 11 full-length ADAMTS13 spacer hybrids was created in which amino acid regions of the spacer domain of ADAMTS13 were exchanged by the corresponding region of the spacer domain of ADAMTS1. Next, the full-length ADAMTS13 spacer hybrids were used in enzyme-linked immunosorbent assay to epitope map anti-spacer autoantibodies in 138 samples from acute and remission iTTP patients. RESULTS: Sixteen different anti-spacer autoantibody profiles were identified with a similar distribution in acute and remission patients. There was no association between the anti-spacer autoantibody profiles and disease severity. Almost all iTTP samples contained anti-spacer autoantibodies against the following three regions: amino acid residues 588-592, 602-610, and 657-666 (hybrids E, G, and M). Between 31% and 57% of the samples had anti-spacer autoantibodies against amino acid regions 572-579, 629-638, 667-676 (hybrids C, J, and N). In contrast, none of the samples had anti-spacer autoantibodies against amino acid regions 556-563, 564-571, 649-656, and 677-685 (hybrids A, B, L, and O). CONCLUSION: We identified three hotspot regions (amino acid regions 588-592, 602-610, and 657-666) in the spacer domain of ADAMTS13 that are targeted by anti-spacer autoantibodies found in a large cohort of iTTP patients.

Open ADAMTS13, induced by antibodies, is a biomarker for subclinical immune-mediated thrombotic thrombocytopenic purpura.

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.

BDNF Plasma Levels and BDNF Exon IV Promoter Methylation as Predictors for Antidepressant Treatment Response.

Major problems of current antidepressant pharmacotherapy are insufficient response rates and difficulties in response prediction. We recently provided preliminary evidence in a small study that patients with major depressive disorder (MDD) with a hypomethylation of the CpG-87 site of the promoter IV region of the brain-derived neurotrophic factor (BDNF) gene are less likely to benefit from antidepressants. Here, we aimed at replicating this finding in a secondary analysis of 561 MDD patients (mean age 40.0 ± 11.9 years, 56% female) included into the Early Medication Change study (EMC). We measured BDNF exon IV promoter and p11 gene methylation at Baseline (BL) as well as BDNF-plasma-levels (pBDNF) at BL and day 14 and related them to treatment outcome. Although we were not able to replicate the predictor function of hypomethylation of the BDNF exon IV promoter, a subgroup of patients with severe depression (Hamilton Depression Rating Scale [HAMD-17] ≥ 25) (n = 199) and hypermethylation at CpG-87 of the BDNF exon IV promoter had significantly higher remission rates than patients without a methylation (p = 0.032). We also found that 421 (75%) of 561 patients showed an early improvement (≥ 20% HAMD-17 reduction after 2 weeks), which was associated with a 4.24-fold increased likelihood to remit at study end compared to the 140 patients without early improvement. However, specificity of response prediction of early improvement was low (34%) and false positive rate high (66%). The combination of early improvement with a pBDNF increase between BL and day 14, however, increased the specificity of response prediction from 34 to 76%, and the combination with methylation of the CpG-87 site of the BDNF exon IV promoter from 34 to 62%. Thus, the combined markers reduced false positives rates from 66 to 24% and 38%, respectively. Methylation at other sites or p11 promoter methylation failed to increase specificity of early improvement prediction. In sum, the results add to previous findings that BDNF, BDNF promoter methylation and the combination of clinical and biological markers may be interesting candidates for therapy response prediction which has to be confirmed in further studies. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00974155, identifier: NCT00974155.

Relapse Rate in Survivors of Acute Autoimmune Thrombotic Thrombocytopenic Purpura Treated with or without Rituximab.

BACKGROUND: Autoimmune thrombotic thrombocytopenic purpura (iTTP) is caused by autoantibody-mediated severe a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) deficiency leading to micro-angiopathic haemolytic anaemia (MAHA) and thrombocytopenia with organ damage. Patients survive with plasma exchange (PEX), fresh frozen plasma replacement and corticosteroid treatment. Anti-CD20 monoclonal antibody rituximab is increasingly used in patients resistant to conventional PEX or relapsing after an acute bout. OBJECTIVE: This retrospective observational study focused on the relapse rate and possible influencing factors including treatment with rituximab first introduced in 2003. PATIENTS AND METHODS: Seventy patients treated between January 2003 and November 2014 were evaluated. Number, duration, clinical manifestations, laboratory data and treatment of acute episodes were documented. Diagnostic criteria of acute iTTP were thrombocytopenia, MAHA, increased lactate dehydrogenase and severe ADAMTS13 deficiency. RESULTS: Fifty-four female and 16 male patients had a total of 224 acute episodes over a median observation period of 8.3 years. The relapse rate was 2.6% per month, for women 2.4% and for men 3.5% per month. Since 2003, 17 patients with a first iTTP episode were treated with rituximab, whereas 28 were not. There was a trend towards lower relapse rates after rituximab treatment over the ensuing years. However, this was statistically not significant. CONCLUSION: This analysis does not show a significant reduction of acute iTTP relapses by rituximab given during an acute bout. Initial episodes are characterized by more severe clinical signs compared with the less severe relapses. Furthermore, men suffer significantly more frequent and considerably more serious acute relapses.

Complement C5 but not C3 is expendable for tissue factor activation by cofactor-independent antiphospholipid antibodies.

The complement and coagulation cascades interact at multiple levels in thrombosis and inflammatory diseases. In venous thrombosis, complement factor 3 (C3) is crucial for platelet and tissue factor (TF) procoagulant activation dependent on protein disulfide isomerase (PDI). Furthermore, C5 selectively contributes to the exposure of leukocyte procoagulant phosphatidylserine (PS), which is a prerequisite for rapid activation of monocyte TF and fibrin formation in thrombosis. Here, we show that monoclonal cofactor-independent antiphospholipid antibodies (aPLs) rapidly activate TF on myelomonocytic cells. TF activation is blocked by PDI inhibitor and an anti-TF antibody interfering with PDI binding to TF, and requires C3 but unexpectedly not C5. Other prothrombotic, complement-fixing antibodies, for example, antithymocyte globulin, typically induce TF activation dependent on C5b-7-mediated PS exposure on the outer membrane of monocytes. We show that aPLs directly induce procoagulant PS exposure independent of C5. Accordingly, mice deficient in C3, but not mice deficient in C5, are protected from in vivo thrombus formation induced by cofactor-independent aPLs. Only immunoglobulin G (IgG) fractions with cofactor-independent anticardiolipin reactivity from patients with antiphospholipid syndrome (APS) induce complement-independent monocyte PS exposure and PDI-dependent TF activation. Neither a human monoclonal aPL directed against ß2-glycoprotein I (ß2GPI) nor patient IgG with selective reactivity to ß2GPI rapidly activated monocyte TF. These results indicate that inhibitors of PDI and TF, but not necessarily clinically available drugs targeting C5, have therapeutic benefit in preventing thrombosis associated with APS caused by pathogenic aPLs primarily reactive with lipid, independent of ß2GPI.

Depression and cognitive deficits as long-term consequences of thrombotic thrombocytopenic purpura.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is an acute life-threatening microangiopathy with a tendency of relapse characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia, and spontaneous von Willebrand factor-induced platelet clumping leading to microthrombi. The brain is frequently affected by microthrombi leading to neurologic abnormalities of varying severity. STUDY DESIGN AND METHODS: The aim of this observational cohort study was to investigate the prevalence of depression and cognitive deficits in 104 patients having survived acute TTP. TTP survivors were repeatedly assessed by means of different standardized questionnaires to evaluate depression (IDS-SR) and mental performance (FLei). We received answers of 104 individual TTP patients and 55 of them participated in both surveys. RESULTS: Seventy-one of the 104 responding TTP patients (68%) suffered from depression and the severity of depression was similar in both surveys performed 1 year apart. Furthermore, TTP patients had considerably lower cognitive performance than controls. There was no correlation between prevalence of depression and cognitive deficits and the number and the severity of acute episodes. Impairment of mental performance correlated with the severity of depression (rs  = 0.779). CONCLUSION: The prevalence of depression and cognitive deficits was significantly higher in TTP patients. Cognitive impairment seemed to be a consequence of depression, almost independently of number and severity of TTP episodes.

Inflammation and psychotropic drugs: the relationship between C-reactive protein and antipsychotic drug levels.

RATIONALE: In psychiatric clinical practice, there is a need to identify psychotropic drugs whose metabolisms are prone to be altered with increased inflammatory activity in an individual patient. OBJECTIVES: The aim of this study was to find out whether elevated serum levels (≥5 mg/l) of C-reactive protein (CRP), an established laboratory marker of infection and inflammation, are associated with increased serum concentrations of the atypical antipsychotic drugs clozapine, quetiapine, and risperidone. METHODS: Therapeutic drug monitoring request forms of patients whose antipsychotic drug concentrations had been measured under conditions of normal (<5 mg/l) and pathological (>5 mg/l) levels of C-reactive protein were retrospectively screened. The serum concentrations in relation to the daily doses [concentration per dose (C/D) (ng/mL/mg)] and the metabolic ratios [ratio of concentrations (metabolite/drug)] were compared intraindividually by the Wilcoxon signed rank test. To the study effects of the intensity of infections on drug concentrations, C-reactive protein and C/D levels were submitted to Spearman's correlation analysis. RESULTS: Elevated levels of C-reactive protein were found in 105 patients. They were significantly associated with elevated values in C/D for clozapine (n = 33, P < 0.01) and risperidone (n = 40, P < 0.01). A trend for an increase was found for quetiapine (n = 32, P = 0.05). Median increases were 48.0 % (clozapine), 11.9 % (quetiapine), and 24.2 % (active moiety of risperidone), respectively. CONCLUSIONS: In patients who exhibit signs of inflammation or infection with increased C-reactive protein values during psychopharmacological treatment, especially under clozapine and risperidone, therapeutic drug monitoring is recommendable in order to minimize the risk of intoxications due to elevated drug concentrations.

Elevated risperidone serum concentrations during acute inflammation, two cases.

Inflammation-mediated changes in drug metabolism may lead to alterations in the absorption, distribution, and clearance of psychotropic drugs and thus elevate drug levels in blood and lead to intoxications. We report about two patients who developed an up to threefold increase of dose-related serum concentrations of risperidone's active moiety (risperidone plus 9-hydroxyrisperidone) during acute inflammation indicated by elevated C-reactive protein. The two female patients (aged 56 and 38 years, respectively) had the diagnoses of paranoid schizophrenia and schizoaffective disorder. For both patients, there was a close time-dependent parallel fluctuation of drug levels and C-reactive protein. Since elevated drug levels could not be attributed to prescribed comedications, it seemed likely that high-serum concentrations of risperidone were due to inflammation. It is concluded that elevated C-reactive protein should be considered as an indication to control blood levels of risperidone and possibly dose adaption.