Thrombotic microangiopathic syndromes associated with drugs, HIV infection, hematopoietic stem cell transplantation and cancer

Thrombotic microangiopathy (TMA) has multiple etiologies. In the four disorders described in this review, the primary organ involved is the kidney. Drug-associated TMA can be an acute, immune-mediated disorder or the result of gradual, dose-dependent toxicity. TMA may occur in patients with advanced HIV infection, possibly mediated by angio-invasive infections. TMA following allogeneic hematopoietic stem cell transplantation may also be caused by drug toxicity; the pathogenesis may involve inhibition of vascular endothelial cell growth factor in renal podocytes. Malignancies of many types with systemic microvascular involvement may cause TMA. Recognition that these syndromes may mimic TTP is important to provide appropriate management and to avoid the inappropriate use of plasma exchange treatment.

Novel ADAMTS13 mutations in an obstetric patient with upshaw-schulman syndrome

Upshaw-Schulman syndrome (USS) is a rarely reported congenital form of thrombotic thrombocytopenic purpura (TTP) that results from mutations in the ADAMTS13 gene. Many USS patients are diagnosed during the second or third trimester of their first pregnancy. We present a patient diagnosed with USS following retinal detachments and intrauterine fetal demise at 34 weeks of gestation. The patient's plasma was tested for ADAMTS13 activity, inhibitor, and antibody. Subsequently, she and her first-degree relatives had ADAMTS13 gene sequencing. Initially, the patient was found to have an ADAMTS13 activity of <5% in the absence of an ADAMTS13 inhibitor (FRETS assay) or antibody (immunoassay). Repeat studies in the months following hospital discharge showed persistent, undetectable ADAMTS13 activity and she was given a clinical diagnosis of USS. Molecular sequencing demonstrated two novel missense mutations in the ADAMTS13 gene: one in the maternal exon 17 (p.Ala690Thr due to nucleotide substitution c.2068 G>A) and another in the paternal exon 22 (p.Arg915Cys due to nucleotide substitution c.2746 C>T). In addition to being compound heterozygous for two ADAMTS13 mutations, the patient also had two maternally inherited single nucleotide polymorphisms: p.P618A (exon 16) and p.A732V (exon 18). Her parents and only sister had normal or near-normal ADAMTS13 activity. Each was heterozygous for one of the novel missense mutations. This case highlights the importance of molecular analysis of the ADAMTS13 gene in patients and family members when the severe ADAMTS13 deficiency does not appear to be autoimmune in nature. J. Clin. Apheresis, 2012. © 2012 Wiley Periodicals, Inc.

Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura

The regulation of VWF multimer size is essential in preventing spontaneous microvascular platelet clumping, a central pathophysiologic finding in thrombotic thrombocytopenic purpura (TTP). In the majority of TTP patients, ADAMTS13, the principal regulator of VWF size, is severely deficient. Today, 2 forms of severe ADAMTS13 deficiency are recognized. The acquired form is caused by circulating autoantibodies inhibiting ADAMTS13 activity or increasing ADAMTS13 clearance. Pathogenic anti-ADAMTS13 Abs are mainly of the IgG class, predominantly of subclass IgG4, and inhibitory Abs recognize a defined epitope in the ADAMTS13 spacer domain. The reasons underlying the failure to maintain immunologic tolerance to ADAMTS13, however, are still poorly understood. Constitutional ADAMTS13 deficiency leading to hereditary TTP, also known as Upshaw-Schulman syndrome, is the result of homozygous or compound heterozygous ADAMTS13 gene mutations.

Late Holocene air temperature variability reconstructed from the sediments of Laguna Escondida, Patagonia, Chile (45 degrees 30 ' S)

Climate and environmental reconstructions from natural archives are important for the interpretation of current climatic change. Few quantitative high-resolution reconstructions exist for South America which is the only land mass extending from the tropics to the southern high latitudes at 56°S. We analyzed sediment cores from two adjacent lakes in Northern Chilean Patagonia, Lago Castor (45°36′S, 71°47′W) and Laguna Escondida (45°31′S, 71°49′W). Radiometric dating (210Pb, 137Cs, 14C-AMS) suggests that the cores reach back to c. 900 BC (Laguna Escondida) and c. 1900 BC (Lago Castor). Both lakes show similarities and reproducibility in sedimentation rate changes and tephra layer deposition. We found eight macroscopic tephras (0.2–5.5 cm thick) dated at 1950 BC, 1700 BC, at 300 BC, 50 BC, 90 AD, 160 AD, 400 AD and at 900 AD. These can be used as regional time-synchronous stratigraphic markers. The two thickest tephras represent known well-dated explosive eruptions of Hudson volcano around 1950 and 300 BC. Biogenic silica flux revealed in both lakes a climate signal and correlation with annual temperature reanalysis data (calibration 1900–2006 AD; Lago Castor r = 0.37; Laguna Escondida r = 0.42, seven years filtered data). We used a linear inverse regression plus scaling model for calibration and leave-one-out cross-validation (RMSEv = 0.56 °C) to reconstruct sub decadal-scale temperature variability for Laguna Escondida back to AD 400. The lower part of the core from Laguna Escondida prior to AD 400 and the core of Lago Castor are strongly influenced by primary and secondary tephras and, therefore, not used for the temperature reconstruction. The temperature reconstruction from Laguna Escondida shows cold conditions in the 5th century (relative to the 20th century mean), warmer temperatures from AD 600 to AD 1150 and colder temperatures from AD 1200 to AD 1450. From AD 1450 to AD 1700 our reconstruction shows a period with stronger variability and on average higher values than the 20th century mean. Until AD 1900 the temperature values decrease but stay slightly above the 20th century mean. Most of the centennial-scale features are reproduced in the few other natural climate archives in the region. The early onset of cool conditions from c. AD 1200 onward seems to be confirmed for this region.

Treatment of thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP), characterized by thrombocytopenia and microangiopathic haemolytic anaemia, was almost universally fatal until the introduction of plasma exchange (PE) therapy in the 1970s. Based on clinical studies, daily PE has become the first-choice therapy since 1991. Recent findings may explain its effectiveness, which may include, in particular, the removal of anti-ADAMTS13 autoantibodies and unusually large von Willebrand factor multimers and/or supply of ADAMTS13 in acquired idiopathic or congenital TTP. Based on currently available data, the favoured PE regimen is daily PE [involving replacement of 1-1.5 times the patient's plasma volume with fresh-frozen plasma (FFP)] until remission. Adverse events of treatment are mainly related to central venous catheters. The potential reduction of plasma related side-effects, such as transfusion-related acute lung injury (TRALI) or febrile transfusion reactions by use of solvent-detergent treated (S/D) plasma instead of FFP is not established by controlled clinical studies. Uncontrolled clinical observations and the hypothesis of an autoimmune process in a significant part of the patients with acquired idiopathic TTP suggest a beneficial effect of adjunctive therapy with corticosteroids. Other immunosuppressive treatments are not tested in controlled trials and should be reserved for refractory or relapsing disease. There is no convincing evidence for the use of antiplatelet agents. Supportive treatment with transfusion of red blood cells or platelets has to be evaluated on a clinical basis, but the transfusion trigger for platelets should be very restrictive. Further controlled, prospective studies should consider the different pathophysiological features of thrombotic microangiopathies, address the prognostic significance of ADAMTS13 and explore alternative exchange fluids to FFP, the role of immunosuppressive therapies and of new plasma saving approaches as recombinant ADAMTS13 and protein A immunoadsorption.

Complementary and conventional medicine in Switzerland: comparing characteristics of general practitioners

OBJECTIVES: Do structural characteristics of general practitioners (GPs) who practice complementary medicine (CAM) differ from those GPs who do not? Assessed characteristics included experience and professional integration of general practitioners (GPs), workload, medical activities, and personal and technical resources of practices. The investigated CAM disciplines were anthroposophic medicine, homoeopathy, traditional Chinese medicine, neural therapy and herbal medicine. MATERIAL AND METHODS: We designed a cross-sectional study with convenience and stratified samples of GPs providing conventional (COM) and/or complementary primary care in Switzerland. The samples were taken from the database of the Swiss medical association (FMH) and from CAM societies. Data were collected using a postal questionnaire. RESULTS: Of the 650 practitioners who were included in the study, 191 were COM, 167 noncertified CAM and 292 certified CAM physicians. The proportion of females was higher in the population of CAM physicians. Gender-adjusted age did not differ between CAM and COM physicians. Nearly twice as many CAM physicians work part-time. Differences were also seen for the majority of structural characteristics such as qualification of physicians, type of practice, type of staff, and presence of technical equipment. CONCLUSION: The study results show that structural characteristics of primary health care do differ between CAM and COM practitioners. We assumed that the activities of GPs are defined essentially by analyzed structures. The results are to be considered for evaluations in primary health care, particularly when quality of health care is assessed.

Physicians' philosophy of care: a comparison of complementary and conventional medicine

BACKGROUND: This project is part of an evaluation of complementary and alternative medicine (CAM) aimed at providing a scientific basis for the Swiss Government to include 5 CAM methods in basic health coverage: anthroposophic medicine, homeopathy, neural therapy, phytotherapy and Traditional Chinese Medicine (TCM). OBJECTIVES: The objective was to explore the philosophy of care (convictions and values, priorities in medical activity, motivation for CAM, criteria for the practice of CAM, limits of the used methods) of conventional and CAM general practitioners (GPs) and to determine differences between both groups. MATERIALS AND METHODS: This study was a cross-sectional survey of a representative sample of 623 GPs who provide complementary or conventional primary care. A mailed questionnaire with open-ended questions focusing on the philosophy of care was used for data collection. An appropriate methodology using a combination of quantitative and qualitative approaches was developed. RESULTS: Significant differences between both groups include philosophy of care (holistic versus positivistic approaches), motivation for CAM (intrinsic versus extrinsic) and priorities in medical activity. Both groups seem to be aware of limitations of the therapeutic methods used. The study reveals that conventional physicians are also using complementary medicine. DISCUSSION: Our study provides a wealth of data documenting several aspects of physicians' philosophy of care as well as differences and similarities between conventional and complementary care. Implications of the study with regard to quality of care as well as ethical and health policy issues should be investigated further.

Health status and health care utilisation of patients in complementary and conventional primary care in Switzerland--an observational study

BACKGROUND: The study is part of a nationwide evaluation of complementary and alternative medicine (CAM) in primary care in Switzerland. OBJECTIVES: Patient health status with respect to demographic attributes such as gender, age, and health care utilisation pattern was studied and compared with conventional primary care. METHODS: The study was performed as a cross-sectional survey including 11932 adult patients seeking complementary or conventional primary care. Patients were asked to document their self-perceived health status by completing a questionnaire in the waiting room. Physicians were performing conventional medicine and/or various forms of complementary primary care such as homeopathy, anthroposophic medicine, neural therapy, herbal medicine, or traditional Chinese medicine. Additional information on patient demographics and yearly consultation rates for participating physicians was obtained from the data pool of all Swiss health insurers. These data were used to confirm the survey results. RESULTS: We observed considerable and significant differences in demographic attributes of patients seeking complementary and conventional care. Patients seeking complementary care documented longer lasting and more severe main health problems than patients in conventional care. The number of previous physician visits differed between patient groups, which indicates higher consumption of medical resources by CAM patients. CONCLUSIONS: The study supports the hypothesis of differences in socio-demographic and behavioural attributes of patients seeking conventional medicine or CAM in primary care. The study provides empirical evidence that CAM users are requiring more physician-based medical services in primary care than users of conventional medicine.