Development Of Thrombotic Microangiopathy Research Articles

Approaches to early detection of atypical hemolytic-uremic syndrome after childbirth

Introduction. Differentiating conditions accompanied by the development of thrombotic microangiopathy (TMA) in obstetrics is still rather challenging. Our present opinion is that the effect of childbirth on the TMA symptom regression is the key to differential diagnosis. If hemolysis and thrombocytopenia regress after childbirth, we can talk about HELLP syndrome. If not, we should think about atypical hemolytic uremic syndrome (aHUS). aHUS is an extremely rare disease characterized by TMA predominantly involving acute kidney injury. However, the diagnostic task can also be difficult due to possible overlapping one process with another: for example, HELLP syndrome can trigger aHUS, but which of the patients is more susceptible to this transformation is unclear.Aim. To identify clinical and laboratory criteria that can be used to early detect aHUS immediately after childbirth.Materials and methods. A total of 230 patients were enrolled in the study, of whom 71 women were diagnosed with aHUS, 124 patients with HELLP syndrome, and 35 patients without signs of TMA were enrolled in the control group. We assessed and compared the main clinical, anamnestic and laboratory findings.Results. Women with HELLP syndrome and aHUS were comparable in terms of age, frequency of operative delivery and gestational age at delivery, and adverse perinatal outcomes. Peak serum creatinine and LDH values after delivery were the most useful to early predict aHUS. Serum creatinine > 142 μmol/L and LDH > 1391 U/L were associated with the transformation of HELLP syndrome into aHUS.Conclusion. We concluded that standard laboratory data, most specifically peak serum creatinine and LDH, may be used to aid in the early diagnosis of aHUS.

Characterizing coagulation responses in humans and nonhuman primates following kidney xenotransplantation-A narrative review.

The recent report of the first pig kidney transplant in a living human brings hope to thousands of people with end-stage kidney failure. The scientific community views this early success with caution as kidney xenotransplantation exhibits many challenges and barriers. One of these is coagulation dysregulation. This includes (i) pig von Willebrand Factor (vWF) interaction with human platelets, which can induce abnormal clotting responses, heightening the risk of graft failure, (ii) the inefficiency of pig thrombomodulin in activating human protein C, which emphasizes the species-specific variations that aggravate coagulation challenges, and (iii) the development of thrombotic microangiopathy in the pig grafts and the occurrence of systemic consumptive coagulopathy in the recipients. Indeed, coagulation dysregulation largely results from differences in endothelial cell response and incompatibilities between pig and human coagulation-anticoagulation pathways. These barriers can be resolved by modifications to pig vWF and the expression of human thrombomodulin and endothelial protein C receptors in pig cells, serving as strategic interventions to align the coagulation systems of the two species more closely. These coagulation challenges have clinical implications in how they affect graft survival and patient outcome. Genetic engineering of the organ-source pig and the administration of various drugs have assisted in correcting this coagulation dysregulation. Hence, comprehending and controlling coagulation dysregulation is crucial for progress in xenotransplantation as a viable option for treating patients with terminal kidney disease.

A Moderate Decrease in ADAMTS13 Activity Correlates with the Severity of STEC-HUS.

Atypical hemolytic uremic syndrome (HUS) develops as a result of damage to the endothelium of microvasculature vessels by Shiga toxin produced by enterohemorrhagic Escherichia coli (STEC-HUS). STEC-HUS remains the leading cause of acute kidney injury (AKI) in children aged 6 months to 5 years. The pathomorphological essence of the disease is the development of thrombotic microangiopathy (TMA). One of the key causes of TMA is an imbalance in the ADAMTS13-von Willebrand factor (vWF)-platelet system. The goal of the work was to clarify the role of a moderate decrease in ADAMTS13 activity in the pathogenesis of STEC-HUS. The activity of ADAMTS13 was determined in 138 children (4 months-14.7 years) in the acute period of STEC-HUS and the features of the course of the disease in these patients were analyzed. The study revealed a decrease in the activity and concentration of ADAMTS13 in 79.8% and 90.6% of patients, respectively. Measurements of von Willebrand factor antigen content and the activity of von Willebrand factor in the blood plasma of part of these patients were carried out. In 48.6% and 34.4% of cases, there was an increase in the antigen concentration and the activity of the Willebrand factor, respectively. Thrombocytopenia was diagnosed in 97.8% of children. We have demonstrated that moderately reduced ADAMTS13 activity correlates with the risk of severe manifestations of STEC-HUS in children; the rate of developing multiple organ failure, cerebral disorders, pulmonary edema, and acute kidney injury with the need for dialysis increases. It is assumed that reduction in ADAMTS13 activity may serve as a predictor of disease severity.

Complement-mediated microvascular injury and thrombosis in the pathogenesis of severe COVID-19: A review.

Coronavirus disease 2019 (COVID-19) causes acute microvascular thrombosis in both venous and arterial structures which is highly associated with increased mortality. The mechanisms leading to thromboembolism are still under investigation. Current evidence suggests that excessive complement activation with severe amplification of the inflammatory response (cytokine storm) hastens disease progression and initiates complement-dependent cytotoxic tissue damage with resultant prothrombotic complications. The concept of thromboinflammation, involving overt inflammation and activation of the coagulation cascade causing thrombotic microangiopathy and end-organ damage, has emerged as one of the core components of COVID-19 pathogenesis. The complement system is a major mediator of the innate immune response and inflammation and thus an appealing treatment target. In this review, we discuss the role of complement in the development of thrombotic microangiopathy and summarize the current data on complement inhibitors as COVID-19 therapeutics.

Regorafenib-induced renal-limited thrombotic microangiopathy: a case report and review of literatures

BackgroundRegorafenib belongs to a sub-group of small-molecule multi-targeted tyrosine kinase inhibitors(TKIs). In various studies with respect to the side-effect of regorafenib, drug-associated proteinuria standardly qualified to be defined as nephrotic syndrome was rarely reported as well as the relation of regorafenib with the occurrence and development of thrombotic microangiopathy (TMA).Case presentationIn this case report and literature review, we presented a 62-year-old patient receiving regorafenib for metastatic colon cancer, manifesting abundant proteinuria, in which TMA was also diagnosed through renal biopsy. As far as we were concerned, this was the first reported in terms of regorafenib-induced TMA confirmed by renal biopsy.ConclusionThis case indicates that regorafenib, a kind of TKIs may result in TMA, which is a rare but life-threatening complication of cancer treatment drug. Insights from this case might help physicians diagnose rare forms of TMA and adjust treatment for patients in a timely manner.

Complement as the enabler of carfilzomib-induced thrombotic microangiopathy.

Carfilzomib has been associated with the development of thrombotic microangiopathy (TMA) in relapsed/refractory multiple myeloma patients, a severe disease with no currently available aetiological treatment. We evaluated the potential role of terminal complement pathway in four patients with carfilzomib-induced TMA. Membrane attack complex (C5b-9) deposition on endothelial cells in culture exposed to plasma from patients during the acute phase of the disease suggests complement overactivation as a mechanism of potential endothelial damage in three out of four patients. If confirmed in larger cohorts, C5b-9 evaluation will allow early identification of patients who could benefit from complement blockade and treatment monitoring.

Predictive Values of Early ST2 for Acute Graft-Versus-Host Disease and Transplant-Related Complications after Allogeneic Stem Cell Transplantation

Background: A soluble form of suppression of tumorigenicity 2 (ST2) has emerged as a biomarker for acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM), whereas a clinical role of ST2 during the early phase of hematopoietic stem cell transplantation (HSCT) has not been fully elucidated. In addition, recent studies have demonstrated that high ST2 levels are associated with the development of thrombotic microangiopathy (TMA) and veno-occlusive disease (VOD) after HSCT. Therefore, we prospectively monitored soluble ST2 levels during the early phase of HSCT and evaluated the clinical association with transplant-related complications including acute GVHD, TMA, and VOD. Methods: Thirty-two adult Japanese patients who received first allogeneic HSCT for hematological diseases were enrolled consecutively between February 2014 and July 2015 at our university hospital or medical center that participate in Yokohama Cooperative Study Group for Hematology (YACHT). The selection of donor source and conditioning regimen was based on patients' hematological diagnosis, donor availability, and patients' clinical status. Soluble ST2 were measured by ELISA at fixed time points (before conditioning, on the day of HSCT (day 0) and days 14, 21, and 28 after HSCT). Serum IL-33 (the ligand of ST2), ferritin and C-reactive protein (CRP) levels were compared with ST2. Results: The median age was 50.5 years (range: 16-66). Acute myeloid leukemia was the main underlying disease (56%). Median soluble ST2 levels on the day of HSCT were higher than baseline and reached the maximum value (92.7 ng/mL (range: 0-419.7)) on day 21 after HSCT. ST2 levels were strongly correlated with ferritin and CRP levels in all samples (r = 0.456 and 0.615). Mainly, ST2 was well correlated with CRP at days 0, 14, and 21 (r = 0.717, 0.630, and 0.628). Serum IL-33 levels were under detection limits in most of the patients, resulting in no correlation of IL-33 with ST2 levels. With a median follow-up of 21.5 months (range: 0.9-35.4), nine patients developed grade II-IV acute GVHD. The optimal cut-off value of soluble ST2 on day 14 for predicting grade II-IV acute GVHD was determined as 100 ng/mL by the ROC analysis. We focused on day 14 ST2 levels as the earliest time point for predicting acute GVHD. The cumulative incidence of acute GVHD was 56.7% and 16.5% in the high and low-ST2 group, respectively (P < 0.01). Multivariate analyses showed that high-ST2 levels at day 14 were associated with a higher incidence of acute GVHD (hazard ratio: 9.35, 95% confidence interval: 2.92-30.0, P < 0.01). Although post-transplant CRP and ferritin levels were correlated with ST2, these markers did not influence the cumulative incidence of acute GVHD. Based on analyses for GVHD severity and the target organ involvement, ST2 levels were not associated with the grade of GVHD, whereas the cumulative incidence of gastrointestinal GVHD was significantly increased in the high-ST2 group (50% vs. 15%, P = 0.03). Finally, we evaluated the association of ST2 levels with other transplant-related complications and mortality. Severe non-GVHD complications were observed in 10 patients, including TMA (n = 2), VOD (n = 5), graft failure (n = 1), engraftment syndrome (n = 4), sepsis (n = 3), and pneumonia (n = 1), which were often overlapped. The cumulative incidence of NRM was increased in the high-ST2 group (33% vs. 0%, P < 0.01), but all the patients died of non-GVHD complications (sepsis, graft failure, TMA, and pneumonia, all of them overlapping with VOD). The two patients who had TMA and five who had VOD were all included in the high-ST2 group. Conclusion: Our detailed analysis regarding serial monitoring of ST2 following HSCT suggests that the early assessment of ST2 may be a predictive indicator for the onset of acute GVHD. Furthermore, we revealed that ST2 levels increased not only in patients with acute GVHD but also in those with other life-threatening complications, such as TMA and VOD, identified during patient monitoring. Although these complications often overlapped each other in the clinical settings for HSCT, gastrointestinal GVHD, TMA, and VOD, all of which are linked to endothelial injury, may be key complications related to high ST2 release. Further studies with larger sample sizes are needed to clarify the clinical value of ST2. Disclosures No relevant conflicts of interest to declare.

Multiple Sclerosis Drug Fingolimod Induces Thrombotic Microangiopathy in Deoxycorticosterone Acetate/Salt Hypertension.

We examined whether fingolimod (FTY720), an S1PR (sphingosine-1-phosphate receptor) modulator, has beneficial or harmful effects on mineralocorticoid/salt-induced renal injury. Uninephrectomized rats on 0.9% NaCl/0.3% KCl drinking solution were randomly divided into control, control+FTY720, deoxycorticosterone acetate (DOCA), and DOCA+FTY720 groups and administered vehicle, vehicle+FTY720, DOCA+vehicle, and DOCA+FTY720 for 4 weeks, respectively. Only the DOCA+FTY720 group had reduced survival rates and showed hemolysis because of intravascular mechanical fragmentation of erythrocytes and thrombocytopenia. Both the DOCA+FTY720 and DOCA groups developed malignant hypertension, which was more severe in the DOCA+FTY720 group. In the DOCA+FTY720 group only, thrombotic microangiopathy involving severe renal arteriole endothelial cell injury was observed and was characterized by fibrinoid necrosis and onion-skin lesions in arterioles. There were fewer circulating endothelial progenitor cells in the DOCA+FTY720 group but more in the DOCA group compared with the control group. Expression levels of VEGF (vascular endothelial growth factor), S1PR1, and S1PR3 in renal arteriole endothelial cells were significantly greater in the DOCA+FTY720 and DOCA groups compared with the control group, with levels being similar between the 2 groups. Expression levels of endothelial nitric oxide synthase in renal arteriole endothelial cells were significantly lower in the DOCA+FTY720 group only. The control+FTY720 group showed reduced circulating endothelial progenitor cells but no significant functional or pathological changes in kidneys or changes in blood pressure. Exposure of uninephrectomized rats to DOCA/salt+FTY720 for 4 weeks induced renal arteriolar endothelial cell injury, resulting in the development of thrombotic microangiopathy. Consideration of this possibility is recommended when prescribing FTY720.

A matched case-control study to assess the association between non-steroidal anti-inflammatory drug use and thrombotic microangiopathy.

Several case reports suggest that non-steroidal anti-inflammatory drug (NSAID) use is associated with development of thrombotic microangiopathy (TMA). We conducted a matched population-based case-control study using linked administrative healthcare data in Ontario, Canada to assess the relationship between TMA hospitalization and recent exposure to prescription NSAIDs versus acetaminophen (acetaminophen was chosen as the referent drug because it has no known association with TMA). Cases and controls were drawn from a source population of adults who filled a prescription for either NSAIDs or acetaminophen between 1991 and 2015 (restricted to adults with prescription drug benefits [n = 3.6 million]). We identified 44 eligible cases with a hospital admission for incident TMA and a recent prescription for NSAIDs or acetaminophen. We successfully matched 38 cases (1:4) to 152 controls without TMA on demographics, risk factors for TMA, and indications for NSAID use. Cases and controls were similar with respect to age (71 years) and sex (63% women); however, on average, cases had more comorbidities than controls (12 vs. 14; p<0.05) and more primary care visits in the year before the index date (19 vs. 12; p<0.05). Cases were significantly less likely than controls to have received a recent prescription for NSAIDs (19/38 [50%] vs. 115/152 [76%], respectively; adjusted odds ratio 0.37, 95% confidence interval: 0.16 to 0.84). Results were similar in several sensitivity analyses. Overall, the results of this study do not support a harmful association between NSAID use and the development of TMA.

Microvesicle Involvement in Shiga Toxin-Associated Infection.

Shiga toxin is the main virulence factor of enterohemorrhagic Escherichia coli, a non-invasive pathogen that releases virulence factors in the intestine, causing hemorrhagic colitis and, in severe cases, hemolytic uremic syndrome (HUS). HUS manifests with acute renal failure, hemolytic anemia and thrombocytopenia. Shiga toxin induces endothelial cell damage leading to platelet deposition in thrombi within the microvasculature and the development of thrombotic microangiopathy, mostly affecting the kidney. Red blood cells are destroyed in the occlusive capillary lesions. This review focuses on the importance of microvesicles shed from blood cells and their participation in the prothrombotic lesion, in hemolysis and in the transfer of toxin from the circulation into the kidney. Shiga toxin binds to blood cells and may undergo endocytosis and be released within microvesicles. Microvesicles normally contribute to intracellular communication and remove unwanted components from cells. Many microvesicles are prothrombotic as they are tissue factor- and phosphatidylserine-positive. Shiga toxin induces complement-mediated hemolysis and the release of complement-coated red blood cell-derived microvesicles. Toxin was demonstrated within blood cell-derived microvesicles that transported it to renal cells, where microvesicles were taken up and released their contents. Microvesicles are thereby involved in all cardinal aspects of Shiga toxin-associated HUS, thrombosis, hemolysis and renal failure.

Early increase of complement terminal pathway activation marker sC5b-9 is predictive for the development of thrombotic microangiopathy after stem cell transplantation

Early increase of complement terminal pathway activation marker sC5b-9 is predictive for the development of thrombotic microangiopathy after stem cell transplantation

Neutrophil Protease Cleavage of Von Willebrand Factor in Glomeruli – An Anti-thrombotic Mechanism in the Kidney

Adequate cleavage of von Willebrand factor (VWF) prevents formation of thrombi. ADAMTS13 is the main VWF-cleaving protease and its deficiency results in development of thrombotic microangiopathy. Besides ADAMTS13 other proteases may also possess VWF-cleaving activity, but their physiological importance in preventing thrombus formation is unknown. This study investigated if, and which, proteases could cleave VWF in the glomerulus. The content of the glomerular basement membrane (GBM) was studied as a reflection of processes occurring in the subendothelial glomerular space. VWF was incubated with human GBMs and VWF cleavage was assessed by multimer structure analysis, immunoblotting and mass spectrometry. VWF was cleaved into the smallest multimers by the GBM, which contained ADAMTS13 as well as neutrophil proteases, elastase, proteinase 3 (PR3), cathepsin-G and matrix-metalloproteinase 9. The most potent components of the GBM capable of VWF cleavage were in the serine protease or metalloprotease category, but not ADAMTS13. Neutralization of neutrophil serine proteases inhibited GBM-mediated VWF-cleaving activity, demonstrating a marked contribution of elastase and/or PR3. VWF-platelet strings formed on the surface of primary glomerular endothelial cells, in a perfusion system, were cleaved by both elastase and the GBM, a process blocked by elastase inhibitor. Ultramorphological studies of the human kidney demonstrated neutrophils releasing elastase into the GBM. Neutrophil proteases may contribute to VWF cleavage within the subendothelium, adjacent to the GBM, and thus regulate thrombus size. This anti-thrombotic mechanism would protect the normal kidney during inflammation and could also explain why most patients with ADAMTS13 deficiency do not develop severe kidney failure.

Carfilzomib: A cause of drug associated thrombotic microangiopathy

Carfilzomib is a selective proteosome inhibitor approved for treatment of relapsed and refractory multiple myeloma. Recent reports have linked exposure to carfilzomib with development of thrombotic microangiopathy (TMA). We describe two cases of biopsy proven thrombotic microangiopathy that occurred after the initiation of carfilzomib (dosed at 32 mg/m2 and 23 mg/m2, respectively) for relapsed multiple myeloma. Both patients were managed with discontinuation of the drug, therapeutic plasma exchange (TPE) and supportive care. Hemoglobin, platelets and renal function did not improve with TPE. TMA resolved with creatinine returning to baseline several weeks after discontinuation of the drug. The outcomes suggest that TPE is not beneficial for treating carfilzomib-induced TMA.

Renal Thrombotic Microangiopathy Associated with the Use of Bortezomib in a Patient with Multiple Myeloma.

Bortezomib is a first-generation proteasome inhibitor used in the treatment of multiple myeloma (MM). A few reports have linked bortezomib exposure with the development of thrombotic microangiopathy (TMA). We describe a case of biopsy-proven renal thrombotic microangiopathy associated with the use of bortezomib in a 51-year-old man with IgG lambda MM. To our knowledge, this is the first biopsy-proven case. In addition, reexposure to bortezomib 18 months later was associated with recurrence of TMA. This supports a possible causal role of bortezomib. The exact mechanisms remain to be elucidated.

Severe obstetric complications as a manifestation of thrombotic microangiopathy

Thrombotic microangiopathy is one of the most serious thrombotic complications characterized by microvascular thrombosis in various organs and accompanied by thrombocytopenia and hemolytic anemia. The term thrombotic microangiopathy has incorporated several nosology, which are characterized by different mechanisms of microvascular thrombosis. Currently thrombotic microangiopathy include thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), heparin-induced thrombocytopenia, HELLP-syndrome. Pregnancy presents one of the key triggers to the development of thrombotic microangiopathy. This fact gives us a significant opportunity to study the pathogenesis of thrombotic microangiopathy in the context of the physiological changes of hemostasis during pregnancy. At the same time the discovery of molecular mechanisms of thrombotic microangiopathy allows for a new research on the field of pathogenesis of thrombotic complications associated with pregnancy, as well as the pathogenesis of so-called placental obstetric complications, including severe preeclampsia, premature detachment of normally situated placenta, septic shock.

Intestinal Ischemia After Allogeneic Stem Cell Transplantation: A Report of Four Cases

Gastrointestinal ischemia after allogeneic bone marrow transplantation is a rare complication not well-described in the literature. Herein we retrospectively review charts of four patients who developed intestinal ischemia after allogeneic bone marrow transplantation at our institution. The patients were found to be predominately younger males who presented with nonspecific abdominal pain. Graft-versus-host disease was a common finding among all patients. Laboratory values suggestive of microangiopathy were present in two patients. Obesity and hypertriglyceridemia were cardiovascular risk factors found in these patients. The development of thrombotic microangiopathy and cardiovascular risk factors after allogeneic bone marrow transplantation may predispose patients to gastrointestinal ischemia and may portend a poor prognosis.

The role of platelets in coagulation dysfunction in xenotransplantation, and therapeutic options

Xenotransplantation could resolve the increasing discrepancy between the availability of deceased human donor organs and the demand for transplantation. Most advances in this field have resulted from the introduction of genetically engineered pigs, e.g., α1,3-galactosyltransferase gene-knockout (GTKO) pigs transgenic for one or more human complement-regulatory proteins (e.g., CD55, CD46, CD59). Failure of these grafts has not been associated with the classical features of acute humoral xenograft rejection, but with the development of thrombotic microangiopathy in the graft and/or consumptive coagulopathy in the recipient. Although the precise mechanisms of coagulation dysregulation remain unclear, molecular incompatibilities between primate coagulation factors and pig natural anticoagulants exacerbate the thrombotic state within the xenograft vasculature. Platelets play a crucial role in thrombosis and contribute to the coagulation disorder in xenotransplantation. They are therefore important targets if this barrier is to be overcome. Further genetic manipulation of the organ-source pigs, such as pigs that express one or more coagulation-regulatory genes (e.g., thrombomodulin, endothelial protein C receptor, tissue factor pathway inhibitor, CD39), is anticipated to inhibit platelet activation and the generation of thrombus. In addition, adjunctive pharmacologic anti-platelet therapy may be required. The genetic manipulations that are currently being tested are reviewed, as are the potential pharmacologic agents that may prove beneficial.

Evaluation Of Laboratory and Clinical Markers For Predicting Survival In TTP/HUS: A Single Center Retrospective Study

BackgroundThrombocytopenic thrombotic purpura (TTP) and hemolytic uremic syndrome (HUS) form a group of diseases distinguishable by the development of thrombotic microangiopathy. Both are life-threatening disorders classically described by a pentad of symptoms: microangiopathic hemolytic anemia, thrombocytopenia, fever, renal failure and altered mental status. Early initiation of plasma exchange (PEX) is vital when TTP/HUS is suspected. However, diagnostic criteria are imprecise and clinical judgment remains the primary impetus for initiation of treatment. ADAMTS13 levels have not proven to be highly specific or sensitive for diagnosis of outcomes in TTP/HUS, and the delay in laboratory reporting limits its use in the acute setting. There may be other data available that more closely correlates with prognosis. The goal of this single institution retrospective study is to assess (i) the association of easily available clinical and laboratory factors with early death in patients with clinically diagnosed TTP/HUS, and (ii) the association of these factors among survivors with the length of stay (LOS) during the initial hospitalization with TTP/HUS. Design and methodsAfter IRB approval, medical record review of adult patients at a single tertiary medical center treated with plasma exchange (PEX) for presumed TTP/HUS between 1999 and May 2013 was performed. For the 62 discrete cases identified, demographic and clinical data was obtained from the medical center and pertinent information was collected. Descriptive analysis was used to evaluate clinical symptoms and laboratory biomarkers with respect to their associations with survival. Episodes of TTP/HUS in the same patient were considered discrete if they occurred greater than 3 months apart. Survival was defined by hospital discharge without readmission for TTP/HUS or their sequelae for 3 months following discharge. The association of demographic factors (age, gender), symptoms (fever, neurologic changes, abdominal pain), and laboratory factors (hemoglobin [Hb], white blood cell count [WBC], platelet count, acute kidney injury [AKI] based on creatinine, AST, ALT, lactate dehydrogenase (LDH), indirect bilirubin, prothrombin time (PT), partial thromboplastin time (PTT), reticulocyte count) with survival during the first 3 months was studied using univariate analysis. ADAMTS13 levels were not included in analysis as the decision to treat with PEX was made in all cases prior to knowledge of any deficiency. All factors that attained a p value of, <= 0.1 were analyzed collectively using logistic regression with backward model selection. For survivors (n=49), the association with length of stay was compared with each of the above factors and was similarly studied using univariate analysis and multiple linear regression. ResultsIn our sample (n=62), median age was 48 years and 26 (42%) were male. Of these, 79% (n=49) survived to discharge and did not have relapse or known death until 3 months afterwards. Thirteen (21%) died during hospitalization or within 3 months after discharge. There were 55 TTP and 7 HUS patients included in this retrospective cohort. Acute kidney injury (AKI) was diagnosed in 44 (71%) patients. On univariate analysis, factors associated with death included: AST (p=0.009) and AKI (p=0.045) with trends noted for hemoglobin (p=0.080) and PT (p=0.078). On multiple logistic regression, association with death was observed with AKI (OR: 0.093, 95% CI 0.009 – 0.950, p= 0.04) and hemoglobin (OR: 0.65, 95% CI 0.434 – 0.975, p=0.037). Among the 49 survivors (median age 45.1, range 12-81 years; 28 (57%) were female), correlation of the LOS in hospital with all variables was assessed. On linear regression analysis, elevated white blood cell count (WBC) (p=0.027) and prolonged prothrombin time (PT) (p=0.035) were independently associated with prolonged hospitalization. ConclusionClinical and laboratory markers found to have an independent association with death are AKI and low hemoglobin. It may be possible to risk stratify patients more accurately with clinical algorithms based on this evidence even before ADAMTS13 levels are available. Increased WBC count and prolonged PT are independently associated with increased length of stay. The application of our results could therefore be used for further risk stratification in prospective studies of outcomes in patients diagnosed with TTP/HUS. Disclosures:No relevant conflicts of interest to declare.

Case of anti‐glomerular basement membrane antibody‐induced glomerulonephritis with cytomegalovirus‐induced thrombotic microangiopathy

Although the involvement of cytomegalovirus (CMV) infections in the development of thrombotic microangiopathy (TMA) in HIV patients and transplant recipients has been reported, it is still controversial whether CMV itself can cause TMA. We report herein a rare case with rapid improvement of TMA by ganciclovir treatment in a patient who is neither HIV-positive nor a transplant recipient, suggesting a pathogenic role for CMV in TMA.

Clinical xenotransplantation: the next medical revolution?

The shortage of organs and cells from deceased individuals continues to restrict allotransplantation. Pigs could provide an alternative source of tissue and cells but the immunological challenges and other barriers associated with xenotransplantation need to be overcome. Transplantation of organs from genetically modified pigs into non-human primates is now not substantially limited by hyperacute, acute antibody-mediated, or cellular rejection, but other issues have become more prominent, such as development of thrombotic microangiopathy in the graft or systemic consumptive coagulopathy in the recipient. To address these problems, pigs that express one or more human thromboregulatory or anti-inflammatory genes are being developed. The results of preclinical transplantation of pig cells--eg, islets, neuronal cells, hepatocytes, or corneas--are much more encouraging than they are for organ transplantation, with survival times greater than 1 year in all cases. Risk of transfer of an infectious microorganism to the recipient is small.