Microangiopathy In Patients Research Articles

Pulmonary tumor thrombotic microangiopathy in patients with gastric carcinoma: An analysis of 6 autopsy cases and review of the literature

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinicopathological entity causing severe pulmonary hypertension (PH). Its histological features include widespread tumor emboli of the small arteries and arterioles of the lung, associated with thrombus formation and fibrocellular and fibromuscular intimal proliferation. Although PTTM has drawn increased attention as a fatal complication of gastric carcinoma (GC), comprehensive studies are still lacking. In order to clarify clinical and pathological features of GC-induced PTTM, recent autopsy cases were analyzed with a review of the literature. Of 36 autopsy cases with GC, 6 (16.7%) were affected by PTTM. Four were male and 2 female, with a mean age of 72.7 years. Three patients presented with PTTM-related clinical manifestations and died of PTTM. They showed clear morphological evidence of PH. The other 3 patients had PTTM as an incidental finding irrespective of clinical manifestations or PH. No patient was diagnosed antemortem as PTTM. All PTTM cases were associated with advanced GC, with a histology of adenocarcinoma of poorly differentiated type ( n = 4) or signet-ring cell type ( n = 2). Expression of tissue factor and vascular endothelial growth factor was confirmed immunohistochemically in tumor cells in all cases. The results were all in line with previous studies. In addition, the current study revealed vascular lesions characteristic of PTTM morphology to be present exclusively in the lung. In conclusion, our study shows a 16.7% incidence of PTTM in GC patients, with half of them developing PH and dying of PTTM, confirming a clinical significance as a non-negligible lethal complication of GC. In addition to many known clinicopathological characteristics of PTTM, the current study pointed to some PTTM issues requiring clarification, including the pathogenesis of the exclusive pulmonary distribution of vascular lesions of PTTM. Since details remain to be elucidated, interdisciplinary research is a high priority with a close collaboration between pathologists and clinicians in order to overcome this lethal condition.

Insulin Resistance is Associated with Microangiopathy in Type 1 Diabetic Patients Treated with Intensive Insulin Therapy from the Onset of Disease

The aim of the study was to evaluate the relationship between indirect parameters of insulin resistance (IR) and risk of microangiopathy in patients with type 1 diabetes (DM1), treated from the initial diagnosis with intensive insulin therapy. The study group consisted of 81 patients with DM1 (51 men, 30 women), aged 34±6.4, and who were observed for 10±1.5 years. Indirect parameters of IR were evaluated: waist circumference, waist to hip ratio (WHR), body mass index (BMI), daily insulin requirement, gain of weight from the beginning of the disease, lipid profile, estimated glucose disposal rate (eGDR), inflammatory markers and features of metabolic syndrome. Patients were divided into two groups depending on the presence or absence of microangiopathy. In the group with microangiopathy (n=36) in comparison with patients without complications (n=45) we found: larger waist circumference (88.9±11.7 vs. 83.7±10.2 cm; p=0.036), higher weight before diabetes (77.3±17.0 vs. 67.0±12.5 kg; p=0.008), higher WHR (0.90±0.08 vs. 0.86±0.08; p=0.048), higher level of triglycerides (1.3±0.8 vs. 0.9±0.3 mmol/l; p=0.002) and lower eGDR (7.2±2.4 vs. 8.8±1.9 mg/kg/min; p=0.0019). In patients with microangiopathy, features of metabolic syndrome were found more often (12 (33.3%) vs. 4 (8.9%); p=0.006). A significant relationship, adjusted for sex, age and duration of diabetes, between eGDR and microangiopathy was revealed (OR 0.65 (95%CI 0.49-0.86); p=0.0037). The results show that in patients with DM1, treated from the initial diagnosis with intensive insulin therapy, there is an independent relationship between IR and the diabetic microangiopathy.

Infection frequently triggers thrombotic microangiopathy in patients with preexisting risk factors: A single‐institution experience

Thrombotic microangiopathies are rare conditions characterized by microangiopathic hemolytic anemia, microthrombi, and multiorgan insult. The disorders, which include hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, are often acute and life threatening. We report a retrospective analysis of 65 patients presenting to our institution from 1997 to 2008 with all forms of thrombotic microangiopathy. Therapeutic plasma exchange was a requirement for analysis and 65 patients were referred to our institution; 66% of patients were female and median age at presentation was 52 years. Bacterial infection was the most commonly identified etiologic factor and in the multivariate model was the only significant variable associated with survival outcome (odds ratio 5.1, 95% confidence interval, 1.2-21.7). As infection can be considered a common trigger event for thrombotic microangiopathy, patients with hepatobiliary sepsis may benefit from elective cholecystectomy. We conclude that bacterial infection frequently triggers TTP and other thrombotic microangiopathies in patients with preexisting risk factors and propose a model for the development of these syndromes.

Endothelin-1 Role in Human Eye: A Review

Endothelin is a potent vasoactive peptide occurring in three isotypes, ET-1, ET-2, and ET-3. Through its two main receptors, endothelin A and endothelin B, it is responsible for a variety of physiological functions, primarily blood flow control. Recent evidence from both human and animal models shows involvement of endothelin in diabetes, retinal circulation, and optic neuropathies. Increased circulating levels of endothelin-1 (ET-1) have been found in patients with diabetes, and a positive correlation between plasma ET-1 levels and microangiopathy in patients with type-2 diabetes has been demonstrated. In addition to its direct vasoconstrictor effects, enhanced levels of ET-1 may contribute to endothelial dysfunction through inhibitory effects on nitric oxide (NO) production. Experimental studies have shown that chronic ET-1 administration to the optic nerve immediately behind the globe causes neuronal damage, activation of astrocytes, the major glial cell in the anterior optic nerve, and upregulation of endothelin B receptors. This paper outlines the ubiquitous role of endothelin and its potential involvement in ophthalmology.

Incidence and Development of Diabetic Microangiopathy of Fulminant Type 1 Diabetes -Comparison with Non-fulminant Type 1 Diabetes-

The data from the Fulminant Type 1 Diabetes Committee suggested that patients with fulminant type 1 diabetes are a subgroup at high risk for diabetic microangiopathy in the first 5 years after diagnosis associated with the lack of endogenous insulin secretion from the onset of diabetes. The aim of this study was to assess the development of microangiopathy in patients with fulminant type 1 diabetes followed in our diabetes center. Sixteen patients with fulminant type 1 diabetes and 60 age-matched patients with non-fulminant type 1 diabetes were recruited as subjects. The existence or lack of diabetic retinopathy and nephropathy, average HbA(1C) level, serum C-peptide level, average blood pressure, insulin level, whether or not they were taking antihypertensive agents, and smoking history were investigated retrospectively based on medical records. The 5-year incidence of microangiopathy was lower in fulminant than in non-fulminant type 1 diabetes patients; retinopathy cases occurred in 0% vs. 8.3% of patients, and nephropathy occurred in 0% vs. 1.7% of patients. The 10-year incidence of retinopathy was 0% vs. 24.1%, and that of nephropathy was 11.1% vs. 3.4%. The cumulative incidence of microangiopathy did not differ between the fulminant and non-fulminant type 1 diabetes patients. Mean HbA(1C) levels and systolic blood pressure were significantly lower in fulminant type 1 diabetes patients. No difference between the patients visiting the center with fulminant type 1 diabetes and those with non-fulminant type 1 diabetes was observed in the development of microangiopathy complications.

Effect of intensive glycemic control on cardiovascular outcomes and all-cause mortality in type 2 diabetes: Overview and metaanalysis of five trials

More intensive diabetes control prevents microangiopathy in patients with both type 1 diabetes and type 2 diabetes. The data related to prevention of macrovascular disease in patients with type 2 diabetes are controversial. The data confirming benefit of the HbA 1c levels below 6.5% came almost exclusively from epidemiological studies. The following article reviews the data from five large clinical randomized trials which compared the more intensive glucose lowering strategy with the standard antidiabetic treatment i.e. UKPDS, PROactive, ACCORD, ADVANCE and VADT. Metaanalysis of five trials showed a highly significant reduction of the incidence of non fatal myocardial infarction [OR 0.84 (95% CI 0.75–0.93), p = 0.001] in patients with intensive glycemic control. No significant differences were observed by combined analysis for the non-fatal stroke, cardiovascular mortality and all-cause mortality between the compared groups. The reason for the discordance of the results of the epidemiological and interventional studies is not clear. The possible explanations could include short duration of the trials to show effect of glucose lowering, as well as attenuating of the beneficial effect of better glycemic control by increased hypoglycemia-related mortality in patients with preexisting cardiovascular disease.

Serum levels of soluble vascular endothelial growth factor receptor-2 in patients with systemic sclerosis

Although vascular endothelial growth factor (VEGF)-A/VEGF receptor 2 (KDR) signalling may play a major role in the microangiopathy of systemic sclerosis (SSc), serum levels of soluble KDR (sKDR) in this disease have not yet been determined. To evaluate the possibility that serum sKDR levels can be a specific disease marker of SSc. Serum sKDR levels of 42 patients with SSc, 10 patients with Raynaud's phenomenon (RP) and 22 healthy controls were measured with specific enzyme-linked immunosorbent assays. Quantitative real-time polymerase chain reaction (PCR) was performed to determine KDR mRNA levels. In females, the serum sKDR levels were significantly higher in patients with SSc, especially limited cutaneous SSc, than in patients with RP or healthy controls. Quantitative real-time PCR with RNA from skin sections revealed that KDR mRNA levels were also increased in the skin of patients with SSc with elevated serum sKDR levels. A significantly lower prevalence of pulmonary fibrosis, higher percentage vital capacity, and a higher incidence of telangiectasia were seen in female patients with SSc with elevated serum sKDR levels than those with normal levels. These results suggest that the skin can be one of the sources of elevated serum sKDR levels, and that serum sKDR levels are useful for diagnosis and may be a marker of microangiopathy in patients with SSc, especially females. The VEGF-A/KDR signalling system may be involved in the pathogenesis of the disease.

Thrombotic microangiopathy in adult-onset Still's disease: case report and review of the literature

Coexistence of thrombotic microangiopathy and adult-onset Still's disease is extremely rare. There is increasing evidence that this association could be more than just coincidental. We report on the case of a 34-year-old male diagnosed with adult-onset Still's disease and successfully treated with intravenous glucocorticoids. Nine months after onset the patient exhibited the presence of asymptomatic thrombocytopenia during treatment with chloroquine. The physical status was unremarkable except for pallor of the skin and mucosa. Laboratory evaluation revealed profound thrombocytopenia and hemolytic anemia. Coombs' tests were negative; renal function tests were all normal. The peripheral blood smear showed frequent schistocytes. Based on the presence of thrombocytopenia and microangiopathic hemolytic anemia, and with the exclusion of other known causes, the patient was diagnosed with thrombotic microangiopathy and successfully treated with plasma exchange and intravenous glucocorticoids. We also review the literature on the association between adult-onset Still's disease and thrombotic microangiopathy; our case is the 15(th) report on such an association. The mean age at onset of adult Still's disease in these cases was 31.60 years and the interval between the diagnosis of Still's disease and the onset of thrombotic microangiopathy ranged from 3 days to 17 years, with a female/male ratio of 2 : 1. In more than half the patients thrombotic microangiopathy occurred within the first 6 months after the diagnosis of the Still's disease. Eleven of the 15 (73%) patients were treated with plasmapheresis in addition to glucocorticoid therapy: eight of 11 (73%) had complete remission, the other three had permanent visual impairment and/or digital ischemia. Of the four patients who were not treated with plasmapheresis, two died, one developed end-stage renal disease and one had complete remission. Awareness of the possible development of thrombotic microangiopathy in patients with adult-onset Still's disease is critical, so that treatment can be initiated early and the complications and recurrence of thrombotic microangiopathy prevented. Patients with adult-onset Still's disease should be closely monitored for signs and symptoms of thrombotic microangiopathy during the first six months after diagnosis of the Still's disease.

Relation between the serum level of C-peptide and risk factors for coronary heart disease and diabetic microangiopathy in patients with type-2 diabetes mellitus.

Syndrome X is used to describe a constellation of factors that lead to coronary heart disease (CHD): hypertension, hyperinsulinemia, impaired glucose tolerance, and an abnormality in lipid metabolism. We investigated the relationship between serum levels of C-peptide immunoreactivity (CPR) and diabetic complications in 256 patients with type-2 diabetes mellitus. The serum level of CPR was measured by radioimmunoassay (RIA). Diabetic patients were divided into 3 groups according to the serum level of CPR as follows: low CPR (n = 19, <0.7 ng/ml), normal CPR (n = 174, 0.7 to 2.2 ng/ml) and high CPR (n = 63, >2.2 ng/ml). The body mass index (BMI) and the serum level of triglycerides were significantly higher in the high CPR group (P < 0.05, respectively) compared with normal CPR group. The prevalence of hypertension was significantly higher in the high CPR group than in the other 2 groups (low CPR: 16%, normal CPR: 28%, high CPR: 38%). The frequency of the number of patients receiving insulin therapy was greater in the low CPR group than in the other 2 groups, (low CPR: 58%, normal CPR: 15%, high CPR: 11%). The serum CPR level was significantly lower in patients with than without proliferative retinopathy or macroalbuminuria. Our conclusion is that the present data suggest that an increased serum level of CPR is associated with obesity, elevated serum triglycerides, and hypertension in patients with type-2 diabetes mellitus. A low CPR level leading to hyperglycemia is associated with the progression of diabetic microangiopathies, such as retinopathy and nephropathy.

Capillaroscopic skin ulcer risk index: A new prognostic tool for digital skin ulcer development in systemic sclerosis patients

Digital ulcerations are one of the most frequent manifestations of microangiopathy in patients with systemic sclerosis (SSc; scleroderma). The early detection of SSc patients who are at high risk to develop digital ulcers could allow a preventive treatment of these complications with reduction of morbidity and social costs. The aim of our study was to develop a capillaroscopic skin ulcer risk index (CSURI) that can predict the onset of new digital ulcers by using nailfold videocapillaroscopy (NVC) in patients with SSc. We performed NVC in 120 consecutive unselected patients with SSc (13 men, 107 women, mean +/- SD age 56.1 +/- 13.4 years, mean +/- SD SSc duration 44.7 +/- 60.7 months) to assess the total number of capillaries in the distal row (N), maximum loop diameter (D), number of megacapillaries (M), and the M:N ratio. Within 3 months since NVC examination, 35 of 120 patients experienced digital ulcers. A significant association between ischemic lesions and the M:N ratio, N, and D was observed; the combination of these parameters allowed us to develop the CSURI, which is characterized by the formula D x M:N(2). A receiver operating characteristic curve analysis showed an area under the curve of 0.926 for ulcer appearance, with specificity and sensitivity of 85.9% and 94.3%, respectively, at the cutoff value of 2.94. Interestingly, 33 of 35 patients with new skin ulcers had a CSURI >2.94, but only 2 of 35 had a CSURI < or =2.94. The proposed CSURI may represent a novel tool with the ability to predict the development of digital ulcers in patients with scleroderma.

Heterogeneous pathogenic processes of thrombotic microangiopathies in patients with connective tissue diseases

To clarify the pathogenic processes of thrombotic microangiopathies (TMAs) in patients with connective tissue disease (CTD), we analysed clinical characteristics and plasma ADAMTS13 levels in 127 patients with CTD-TMAs, including patients with systemic lupus erythematosus (SLE), systemic sclerosis, polymyositis/dermatomyositis, and rheumatoid arthritis (RA), and 64 patients with acquired idiopathic thrombotic thrombocytopenic purpura (ai-TTP). Plasma levels of ADAMTS13 activity, antigen, and inhibitors were determined by enzyme immunoassays. IgG type anti-ADAMTS13 antibodies were also detected by immunoblots using purified ADAMTS13. ADAMTS13 activity was significantly decreased in CTD-TMAs, regardless of the underlying disease, but the frequency of severe deficiency (defined as <0.5% of normal) was lower in CTD-TMA patients than in ai-TTP patients (16.5% vs. 70.3%, p < 0.01). Severe deficiency of ADAMTS13 activity was predominantly detected in patients with RA- and SLE-TMAs, and was closely associated with the presence of anti-ADAMTS13 IgG antibodies. CTD-TMA patients with severe deficiency of ADAMTS13 activity appeared to have lower platelet counts and better therapeutic outcomes. At least two phenotypic TMAs occur in patients with CTDs: a minor population with deficient ADAMTS13 activity caused by neutralising autoantibodies, and a major population with normal or moderately reduced activity. Classifying CTD-TMAs by ADAMTS13 activity may be useful in predicting the clinical course and therapeutic outcomes, as patients with moderately reduced activity are likely to have more prominent renal impairment and poor prognoses.

Elevated procalcitonin and C‐reactive protein as potential biomarkers of sepsis in a subpopulation of thrombotic microangiopathy patients

Thrombotic microangiopathy (TMA) comprises a group of microvascular thrombosis syndromes associated with multiple pathogenic factors. Deficient activity of ADAMTS13 is a pathogenic factor in a subset of TMA patients that provides a strong rationale for plasma exchange treatment. However, the subset of TMA patients with normal ADAMTS13 activity remains a heterogeneous group of patients in which the appropriate treatment is not well understood. In addition to the common forms of TMA thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome, the differential diagnosis of TMA may include sepsis, autoimmune disorders, and disseminated intravascular coagulation. Optimal treatment of TMA depends on timely recognition of treatable pathogenic factors. We hypothesized that sepsis is a rapidly identifiable pathogenic factor in a subset of TMA patients. To test this hypothesis, we retrospectively measured the rapid biomarkers of sepsis C-reactive protein (CRP) and procalcitonin (PCT), in a repository of pretreatment plasma samples from 61 TMA patients treated with plasma exchange. Levels were analyzed in 31 severely ADAMTS13-deficient and 30 ADAMTS13-normal patients. None of the 31 patients with severe deficiency of ADAMTS13 had elevated PCT. However, 11 of 30 (37%) non-ADAMTS13-deficient patient samples were strongly positive for PCT. These patient samples also had a >10-fold higher median CRP level than patients with normal PCT. We conclude that rapid assays may help identify sepsis in a subset of TMA patients.

Thrombotic Microangiopathy in Patients with Allogeneic Hematopoietic Stem Cell Transplantation

Background : Transplantation-associated thrombotic microangiopathy (TMA) is infrequent but devastating complications after allogeneic hematopoietic stem cell transplantation (HSCT). However, there were no widely accepted criteria for the definition of TMA. Recently, the Blood and Marrow Transplants Clinical Trials Network (BMT CTN) and International Working Group (IWG) proposed a definition for TMA with some differences. The BMT CTN defined TMA as an increased number of schistocytes (3 2/high power field (HPF)) and elevated lactate dehydrogenase (LDH), concurrent renal and/or neurologic dysfunction, and negative Coombs' test results. On the other hand, the IWG defined TMA by adding prolonged or progressive thrombocytopenia, a decrease in hemoglobin and serum haptoglobin concentration instead of concurrent renal and/or neurologic dysfunction and negative Coombs' test results. In addition, the value of an increased number of schistocytes (34% or 3 8/HPF) for diagnosis of TMA by IWG is higher than that by BMT CTN (3 2/HPF). Until now, there has been no report to validate both criteria for TMA.Patients and Methods : We retrospectively examined 672 consecutive patients (median age 34 years, range 15–68) who underwent allogeneic HSCT from matched sibling donor (n = 442) and alternative donor (n = 230) at Catholic HSCT Center between January 2002 and December 2006 to analyze the role of some predicting factors for the incidence and outcome of TMA after HSCT and to validate two recently proposed criteria for TMA. We defined TMA as an increased number of schistocytes (3 2/HPF), elevated LDH, prolonged or progressive thrombocytopenia, a decrease in hemoglobin and serum haptoglobin concentration, and negative Coombs' test results (O-TMA). O-TMA with renal and/or neurologic dysfunction was compatible with TMA defined by BMT CTN (B-TMA), and O-TMA with increased number of schistocytes over 8/HPF was compatible with TMA defined by IWG (I-TMA). TMA-associated death was defined as the interval from the onset of TMA to death which was associated with TMA without a relapse from underlying diseases after the onset of TMA.Results : Among 672 patients, 85 patients (13%) developed O-TMA including 41 patients (6%) with B-TMA and 17 patients (3%) with I-TMA. On multivariate analysis, TMA occurrence was higher in patients with older age (P = 0.001), mismatched human leukocyte antigen (P < 0.001), and acute graft-versus-host disease (GVHD) 3 grade II (P < 0.001) for O-TMA, in patients with older age (P = 0.002), advanced disease status at HSCT (P = 0.005), and acute GVHD 3 grade II (P < 0.001) for B-TMA, and advanced disease status at HSCT (P = 0.017) and acute GVHD 3 grade III (P < 0.001) for I-TMA. In patients with O-TMA, patients with renal dysfunction (hazard ratio 4.03, 95% CI 2.38–6.83, P < 0.001) and/or concurrent veno-occlusive disease (hazard ratio 3.16, 95% CI 1.50–6.62, P = 0.002) proved to have significantly decreased overall survival by multivariate analysis. In addition, the presence of renal dysfunction was the only significant factor associated with increased TMA-associated death (hazard ratio 11.61, 95% CI 4.79–28.16, P < 0.001). Maximal schistocytes count over 8/HPF and other factors including sex mismatch, acute GVHD 3 grade III, advanced disease status at HSCT, maximal LDH over 1298 IU/l, neurologic dysfunction, and concurrent cytomegalo virus infection that were significant on univariate analysis failed to show the significance relationship on multivariate analysis.Conclusions : This study identifies which patients are more prone to developing TMA after allogeneic HSCT according to three definitions for TMA (O-TMA, B-TMA and I-TMA). Notably, using multivariate analysis in patients with O-TMA, this retrospective study shows the importance of renal dysfunction compared to the maximal number of schistocytes count, which suggests that there are possible shortcomings of the definition by I-TMA that can miss out those with schistocytes count less than 8/HPF who may need early detection as a TMA. The proposed definitions of TMA need to be modified and be validated with prospective studies.

The importance of endothelin-1 for microvascular dysfunction in diabetes

Most of the late diabetic complications such as retinopathy, nephropathy, and neuropathy, have their basis in disturbed microvascular function. Structural and functional changes in the micro-circulation are present in diabetes mellitus irrespective of the organ studied, and the pathogenesis is complex. Endothelial dysfunction, characterized by an imbalance between endothelium-derived vasodilator and vasoconstrictor substances, plays an important role in the pathogenesis of diabetic microangiopathy. Increased circulating levels of endothelin-1 (ET-1), a potent vasoconstrictor peptide, has been found in patients with diabetes, and a positive correlation between plasma ET-1 levels and microangiopathy in patients with type 2 diabetes has been demonstrated. In addition to its direct vasoconstrictor effects, enhanced levels of ET-1 may contribute to endothelial dysfunction through inhibitory effects on nitric oxide (NO) production. Vascular endothelial dysfunction may precede insulin resistance, although the feature of insulin resistance syndrome includes factors that have negative effects on endothelial function. Furthermore, ET-1 induces a reduction in insulin sensitivity and may take part in the development of the metabolic syndrome. In the following, the mechanisms by which ET-1 contributes to the development of diabetic microangiopathy and the potentially beneficial effect of selective ET(A) receptor antagonists are discussed.

Transplant-Associated Microangiopathy in Patients Receiving Tacrolimus Following Allogeneic Stem Cell Transplantation: Risk Factors and Response to Treatment

Transplant-associated microangiopathy (TAM) is a life-threatening complication after allogeneic HSCT, particularly with the use of calcineurin inhibitors as post-transplantation immunosuppressive therapy. We report our experience with TAM after HSCT with tacrolimus-based GVHD prophylaxis in a single-center study. Sixty-six of 1219 transplant recipients developed TAM with a cumulative incidence of 5.9%. Risk factors for TAM were female gender, lymphoid malignancy, receipt of a matched unrelated donor, and grade II-IV aGVHD. Most patients had infection and/or active GVHD at the diagnosis of TAM (82%). In the absence of renal dysfunction or encephalopathy, tacrolimus was generally continued, maintaining blood levels within the lower therapeutic range. Sixty-three patients were treated with plasma exchange. The cumulative incidence of response of TAM was 60%. Only 1 patient had a response of TAM without resolution of concomitant infections or GVHD. Six-month survivals were 0% and 50% for TAM nonresponders and responders, respectively. In conclusion, TAM is a common, life-threatening complication of allogeneic hematopoietic transplantation using tacrolimus prophylaxis. Control of TAM generally requires response of associated infections and GVHD. TMA response may occur despite continuation of tacrolimus treatment.

Fulminant type 1 diabetes as a high risk group for diabetic microangiopathy—a nationwide 5-year-study in Japan

The aim of the present study was to assess the development of microangiopathy in patients with fulminant type 1 diabetes, a novel subtype of type 1B diabetes. In a nationwide survey, we followed 41 patients with fulminant type 1 diabetes and 76 age- and sex-matched patients with type 1A diabetes for 5 years. The following data were recorded every 12 months after the onset of diabetes: seven-point blood glucose concentrations, HbA1c level, urinary albumin excretion, serum C-peptide level, blood pressure, daily dosages of insulin, frequency of severe hypoglycaemic episodes, and neurological and fundoscopic examination. The 5-year cumulative incidence of microangiopathy was 24.4% in fulminant type 1 diabetes and 2.6% in type 1A diabetes. In longitudinal studies using the Kaplan-Meier method, the cumulative incidence of each form of microangiopathy was significantly higher in fulminant type 1 diabetes than in type 1A diabetes; retinopathy was 9.8% vs 0% (p=0.014), nephropathy 12.2% vs 2.6% (p=0.015) and neuropathy 12.2% vs 1.3% (p=0.010), respectively. Mean HbA1c levels were similar in the fulminant and type 1A diabetes groups during the follow-up periods. However, the mean M-value, mean insulin dosages and the frequency of severe hypoglycaemic episodes were significantly higher, and the mean postprandial C-peptide level was significantly lower in the fulminant type 1 diabetes group. These data suggest that patients with fulminant type 1 diabetes are a high-risk subgroup for diabetic microangiopathy associated with the lack of endogenous insulin secretion from the onset of diabetes.

Carbon disulfide encephalopathy: Cerebral microangiopathy

To understand cerebral blood circulation after long-term exposure to carbon disulfide (CS 2), four patients with encephalopathy and polyneuropathy, who had worked in a viscose rayon plant, were studied. Clinical and laboratory examinations, including brain magnetic resonance images (MRI), computed tomography (CT), CT perfusion, and CT angiography, were carried out. Brain CT and MRI disclosed mild cortical atrophy in all four patients, and multiple lesions in the subcortical white matter, and basal ganglia in three patients. Brain CT angiography and perfusion revealed a statistically significant decrease of cerebral blood flow (CBF) in the total brain parenchyma and basal ganglia, and a decrease of the cerebral blood volume (CBV) in the basal ganglia and a prolonged mean transit time (MTT) in the total brain parenchyma, and the territories of the internal carotid artery (ICA), basal ganglia and occipital lobe. In conclusion, the decrease of CBV and CBF, and the prolonged MTT in the total brain parenchyma, ICA, basal ganglia and occipital lobes, indicated a microangiopathy in patients with CS 2 encephalopathy.

Time course of organ dysfunction in thrombotic microangiopathy patients receiving either plasma perfusion or plasma exchange*

Few studies have investigated adults with thrombotic microangiopathy (TMA) requiring intensive care unit (ICU) admission, and the treatment remains controversial. To describe causes, outcomes, prognostic factors, and daily organ-failure score changes in adults with TMA requiring ICU admission. A 3-yr single-center cohort study. The patients were 36 adults with TMA admitted to a teaching-hospital medical ICU between January 2000 and June 2003. Of the 36 patients, 22 received plasma infusion and 15 underwent plasma exchange. All patients had anemia and thrombocytopenia at ICU admission, and 13 had neurologic impairment. Median creatinine clearance was 55.2 mL/min (interquartile range, 28.8-75.4). No patient had congenital TMA. Causative factors included microbiologically documented infection in 14 patients, allogeneic transplantation in 7 patients, and concomitant or subsequent systemic disease in 7 patients; 6 patients were human immunodeficiency virus-positive, 5 had drug-induced TMA, 2 were pregnant, and 2 had cancer. In 10 patients, no causative factors were identified. Plasma exchange was associated with a statistically significant decrease in hospital mortality (0 vs. 7 deaths; p < .001). Moreover, daily organ-failure scores were significantly lower in the plasma-exchange group from day 3 to day 9. Patients in the plasma-exchange group received a larger volume of plasma. Plasma exchange may be associated with faster resolution of organ failure and with improved survival for patients with TMA requiring ICU admission.

Pulsatility Index at the Cervical Internal Carotid Artery as a Parameter of Microangiopathy in Patients With Type 2 Diabetes

Although carotid intima-media thickness is a well-recognized indicator of atherosclerosis, it may not be an appropriate indicator of microangiopathy. We evaluated the parameters of extracranial carotid artery (CA) duplex ultrasonographic scanning in relation to microalbuminuria, which is an indicator of microangiopathy in patients with diabetes. The relationships of CA stenosis, hypertension, and dyslipidemia with microalbuminuria were also evaluated. Among 234 patients who were hospitalized for controlling type 2 diabetes during a 20-month period, those with major cerebrovascular, cardiac, or renal disease were excluded, leaving 159 patients who did not have any acute symptoms enrolled in this cross-sectional study. The parameters of extracranial CA duplex ultrasonographic scanning and urine albumin-to-creatinine ratio (u-ACR) were extracted, and their relationships were analyzed. Each patient's status with regard to CA stenosis, hypertension, and dyslipidemia was also examined for the effects on u-ACR. Of the 159 patients, 29 (18.2%) had some CA stenosis, and there were significantly more hypertensive patients in this group (P=.007). The value of u-ACR was significantly higher in patients with dyslipidemia (P<.001) but not in those with CA stenosis or hypertension. With univariate analysis, significant correlations of u-ACR were observed with age, right end-diastolic velocity, and the bilateral pulsatility index (PI). Among these factors, multivariate analysis was made, and only age and PI proved to be independent factors correlated with u-ACR (P<.0001). With a PI cutoff of 1.15, 89.3% specificity with 49.1% sensitivity was obtained for detecting microalbuminuria. The PI at the cervical internal CA can indicate microangiopathy because of its strong correlation with microalbuminuria in patients with type 2 diabetes, and it is thought to reflect the microangiopathy of cerebral vessels.

Novel compound heterozygote mutations (H234Q/R1206X) of the ADAMTS13 gene in an adult patient with Upshaw–Schulman syndrome showing predominant episodes of repeated acute renal failure

Unlike acquired thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome, which are often intractable, thrombotic microangiopathy in patients with Upshaw-Schulman syndrome (USS)--a congenital deficiency of von Willebrand factor-cleaving protease (ADAMTS13) activity--responds very well to plasma infusion and does not even require plasma exchange. However, the symptoms significantly vary in each individual and thus clinicians often overlook this diagnosis. A 31-year-old adult male patient with thrombotic microangiopathy, which was complicated with repeated episodes of acute renal failure, is reported. We suspected that the patient had USS and performed assays of ADAMT13 activity and its inhibitor, followed by ADAMTS13 gene analysis of the patient and his parents. The patient had extremely low ADAMTS13 activity and has no inhibitors of ADAMTS13. Through an ADAMTS13 gene analysis of this family, we found two novel mutations responsible for the disease: a missense mutation in exon 7 [702 C --> A (H234Q)] from the father and a nonsense mutation in exon 26 [3616 C --> T (R1206X)] from the mother. Our experience appears to indicate the importance of assays of ADAMTS13 activity and its inhibitor in patients who have episodes of renal insufficiency in association with thrombotic microangiopathy, for diagnosis and choice of treatment.