Onset Of Thrombotic Microangiopathy Research Articles

#550 Characteristics of patients with aHUS who discontinued dialysis after eculizumab treatment: sub-analysis of post-marketing surveillance in Japan

Abstract Background and Aims Atypical haemolytic uraemic syndrome (aHUS), a type of thrombotic microangiopathy (TMA), is a disease accompanied by acute kidney injury which typically requires dialysis in half of the patients. Eculizumab is the first complement C5 inhibitor approved for aHUS in Japan. Early treatment initiation with eculizumab is associated with better renal outcomes, and dialysis withdrawal has been observed in some of patients on dialysis after treatment with eculizumab. However, patient characteristics relating to dialysis continuation or withdrawal after treatment with C5 inhibitors have not been investigated. Method Paediatric and adult patients with aHUS who were enrolled in Japanese post-marketing surveillance (PMS) for eculizumab and who were on dialysis at the initiation of eculizumab treatment were included in this analysis. Characteristics and clinical courses were compared in two groups: patients who discontinued dialysis within 26 weeks from initiation of eculizumab (Group A) and those who stayed on dialysis for 26 weeks (Group B). Results Among 38 patients included in this analysis, 21 patients (55%) discontinued dialysis (Group A) and 17 patients (45%) stayed on dialysis (Group B). The proportion of paediatrics/adults (7/14 vs. 2/15, P = 0.148), median age (6 vs. 8 years old, P = 0.88 and 54.5 vs. 62 years old, P = 0.47), and the proportion of patients with/without complement-related gene variants or anti-CFH antibody (9/8 vs. 6/5, P = 1.000) were comparable between the two groups. Meanwhile, the proportion of patients with hypertension at baseline was significantly lower in Group A than in Group B (6/21 vs. 11/17, P = 0.022). The median duration of dialysis before initiation of eculizumab (6.0 days vs. 17.0 days, P = 0.011) and the median time from TMA onset to eculizumab initiation (9.0 days vs. 25.0 days, P = 0.008) were significantly shorter in Group A than in Group B, respectively. In contrast, there was no significant difference in the median time from TMA onset to initiation of plasma therapy between the two groups (3.5 days vs. 8.0 days, P = 0.154). No significant difference was also observed in the median (range) duration of eculizumab treatment [75 (13-241) weeks vs. 40 (12-256) weeks, P = 0.167]. Stepwise multivariate logistic regression analysis showed that the time from TMA onset to eculizumab initiation (<15 days/≥15 days) was an independent factor associated with the withdrawal of dialysis (P = 0.013), but the existence of hypertension at baseline as a complication and patients age (paediatrics/adults) were not (P = 0.157 and P = 0.869). No patients in Group A restarted dialysis after dialysis discontinuation. Five out of 17 patients in Group B discontinued dialysis after 27 weeks; their median (range) time to dialysis withdrawal was 63 (27-184) weeks. Conclusion These results demonstrate that early initiation of C5 inhibitors can offer the chance of renal recovery and no further need for dialysis. Continuing treatment with C5 inhibitor beyond 26 weeks may also offer the chance to discontinue dialysis for some patients.

Thrombotic Microangiopathy as a Life-Threatening Complication of Long-Term Interferon Beta Therapy for Multiple Sclerosis: Clinical Phenotype and Response to Treatment-A Literature Review.

Thrombotic microangiopathy (TMA) has been observed in some patients receiving interferon beta (IFNβ) therapy for relapsing-remitting multiple sclerosis, but little is known about its clinical features and outcomes. We searched the literature to identify cases with IFNβ-related TMA and assessed their pattern of organ involvement, the presence of prodromal manifestations, the treatments used, and the outcomes. Thirty-five articles met the inclusion criteria, and data of 67 patients were collected. The median duration of IFNβ therapy before the diagnosis of TMA was 8 years, and 56/67 (84%) presented with acute kidney injury (AKI), of which 33 required acute dialysis. All but three patients had manifestations during the four weeks before TMA onset, including flu-like symptoms, headache, and worsening blood pressure control. In only two patients, ADAMTS13 activity was reduced, while 27% had low C3 levels. However, none showed causative genetic mutations associated with development of atypical hemolytic uremic syndrome. All patients discontinued IFNβ, 34 (55%) also received plasma exchange, and 12 (18%) received eculizumab. Complete renal recovery was achieved by 20 patients (30%), while 13 (20%) developed end-stage renal disease. Among those with AKI requiring dialysis, eculizumab therapy was associated with a significantly reduced risk of ESRD compared with plasma exchange. Therefore, TMA with features of aHUS mainly occurs after prolonged treatment with IFNβ and is preceded by prodromes, which may lead to an early diagnosis before life-threatening complications occur. Eculizumab appears beneficial in cases with severe kidney involvement, which supports a role of the complement system in the pathogenesis of these forms.

Application of a scoring system in Japanese patients diagnosed with atypical hemolytic uremic syndrome to assess the relationship between the score and clinical responses to eculizumab

BackgroundAtypical hemolytic uremic syndrome (aHUS) is caused by complement dysregulation and is generally diagnosed by exclusion from other disorders of thrombotic microangiopathy (TMA). Eculizumab, a terminal complement inhibitor, has been approved for aHUS treatment since 2013 in Japan. Recently, a scoring system was published to support diagnosis of aHUS. Herein we modified this scoring system to apply it to patients diagnosed with aHUS and treated with eculizumab, and assessed the association between the score and clinical responses to eculizumab.MethodsOne hundred eighty-eight Japanese patients who were clinically diagnosed with aHUS, treated with eculizumab, and enrolled in post-marketing surveillance (PMS) were included in this analysis. Some of parameters in the original scoring system were replaced with clinically similar parameters collected in the PMS to modify the system, hereafter referred to as the TMA/aHUS score, which ranges from -15 to 20 points. Treatment responses within 90 days after eculizumab initiation were also assessed, and the relationship between treatment response and TMA/aHUS scores calculated at TMA onset was explored.ResultsThe median (range) TMA/aHUS score was 10 (3–16). Receiver operating characteristic curve analysis showed that the cutoff value of TMA/aHUS score to predict treatment response to eculizumab was estimated as 10, and negative predictive value indicated that ≥ 5 points was appropriate to consider assessing the treatment response to eculizumab; 185 (98%) patients had ≥ 5 points and 3 (2%) had < 5 points. Among the patients with ≥ 5 points, 96.1% showed partial response and 31.1% showed complete response. One of the three patients with < 5 points met partial response criteria. No significant difference in the TMA/aHUS scores was observed between survivors and non-survivors, suggesting that the score was not appropriate to predict the outcome (i.e., survival/death) in patients treated with eculizumab.ConclusionAlmost all patients clinically diagnosed with aHUS scored ≥ 5 points and responded to eculizumab. The TMA/aHUS score system could become a supporting tool for the clinical diagnosis of aHUS and probability of response to treatment with a C5 inhibitor.Trial registrationThis study was conducted as per good PMS practice guidelines for drugs (MHLW Ministerial Ordinance No. 171 of 2004).

Bleeding and Thrombosis: Insights into Pathophysiology of Bothrops Venom-Related Hemostasis Disorders.

Toxins from Bothrops venoms targeting hemostasis are responsible for a broad range of clinical and biological syndromes including local and systemic bleeding, incoagulability, thrombotic microangiopathy and macrothrombosis. Beyond hemostais disorders, toxins are also involved in the pathogenesis of edema and in most complications such as hypovolemia, cardiovascular collapse, acute kidney injury, myonecrosis, compartmental syndrome and superinfection. These toxins can be classified as enzymatic proteins (snake venom metalloproteinases, snake venom serine proteases, phospholipases A2 and L-amino acid oxidases) and non-enzymatic proteins (desintegrins and C-type lectin proteins). Bleeding is due to a multifocal toxicity targeting vessels, platelets and coagulation factors. Vessel damage due to the degradation of basement membrane and the subsequent disruption of endothelial cell integrity under hydrostatic pressure and tangential shear stress is primarily responsible for bleeding. Hemorrhage is promoted by thrombocytopenia, platelet hypoaggregation, consumption coagulopathy and fibrin(ogen)olysis. Onset of thrombotic microangiopathy is probably due to the switch of endothelium to a prothrombotic phenotype with overexpression of tissue factor and other pro-aggregating biomarkers in association with activation of platelets and coagulation. Thrombosis involving large-caliber vessels in B. lanceolatus envenomation remains a unique entity, which exact pathophysiology remains poorly understood.

Two cases of carfilzomib\u2010induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma

BackgroundTreatment with proteasome inhibitors like carfilzomib in patients with multiple myeloma (MM) can induce thrombotic microangiopathy (TMA) characterized by neurological symptoms, acute kidney injury, hemolysis and thrombocytopenia. Successful treatment with the monoclonal antibody eculizumab was described for these patients, but reports of ideal management and definitive treatment protocols are lacking.Case PresentationThe first case describes a 43-years-old IgG-kappa-MM patient that developed TMA during the first course of carfilzomib-lenalidomide-dexamethasone (KRd) consolidation after autologous stem cell transplantation (ASCT). In the second case, a 59-years-old IgG-kappa-MM patient showed late-onset TMA during the fourth and last cycle of elotuzumab-KRd consolidation within the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Concurrently, he suffered from influenza A/B infection. Both patients had a high TMA-index for a poor prognosis of TMA. Therapeutically, in both patients plasma exchange (TPE) was initiated as soon as TMA was diagnosed. In patient #1, dialysis became necessary. For both patients, only when the complement inhibitor eculizumab was administered, kidney function and blood values impressively improved.ConclusionIn this small case series, two patients with MM developed TMA due to carfilzomib treatment (CFZ-TMA), the second patient as a late-onset form. Even though TMA could have been elicited by influenza in the second patient and occurred after ASCT in both patients, with cases of TMA post-transplantation in MM being described, a relation of TMA and carfilzomib treatment was most likely. In both patients, treatment with eculizumab over two months efficiently treated TMA without recurrence and with both patients remaining responsive months after TMA onset. Taken together, we describe two cases of TMA in MM patients on carfilzomib-combination treatment, showing similar courses of this severe adverse reaction, with good responses to two months of eculizumab treatment.

Coagulation disorders in SARS-CoV-2 infection.

A better understanding of the pathogenetic mechanisms triggered by SARS-CoV-2 infection may contribute to a more effective management of patients with COVID-19. Coagulation dysfunction is a key pathogenetic element of this disease as well as a challenge for practitioners. Marked inflammatory process found in severe forms of COVID-19, the complement activation, the cytokine storm, and disruption of the renin-angiotensin-aldosterone system are involved in the onset of thrombotic microangiopathy and large vessel coagulopathy. Virus-induced procoagulant activity occurs at the systemic level. Intravascular microthrombi disrupt vascularization in various tissues and organs, contributing to the occurrence of multiorgan failure and explain the higher morbidity and all-cause mortality of patients. It is estimated that almost 20% of patients with COVID-19 have significant coagulation disorders, and about a quarter of those hospitalized in intensive care units are prone to develop thrombosis events under prophylactic anticoagulant treatment. Some of patients who have been immunized after healing from the SARS-CoV-2 infection have a hypercoagulable state and are prone to develop thrombosis. Hypercoagulability is supported by thrombelastographic analysis: patients have an acceleration of the propagation phase of blood clot formation and higher clot strength. Markers of coagulation dysfunction in SARS-CoV2 are: decreased platelet count, increased INR, presence of fibrin degradation products, and especially higher plasma levels of D-dimers, which predict unfavorable outcome in these patients. Age, pre-existing diseases and associated risk factors, together with careful monitoring of clinical evolution and laboratory parameters allow the choice of the best personalized prophylactic or curative anticoagulant treatment.

Late renal recovery after treatment over 1\u2009year post-onset in an atypical hemolytic uremic syndrome: a case report

BackgroundAtypical hemolytic uremic syndrome (aHUS) is a life-threatening disease that leads to end-stage kidney disease if only a poor response to plasma exchanges (PEs) or eculizumab therapy is achieved.Case presentationA 58-year-old Japanese man presented with thrombocytopenia, anemia, and kidney failure requiring dialysis without any underlying disease. A kidney biopsy revealed marked mesangiolysis in all glomeruli, compatible with thrombotic microangiopathy (TMA). Based on the positive anti- factor H antibody and negative result for secondary TMA, we diagnosed him as aHUS. Despite eculizumab administration after eight sessions of PE, neither platelet normalization nor kidney recovery was achieved. Eight months later, we discontinued eculizumab therapy due to anaphylactic reaction. At 15 months after the onset of TMA, his platelet count increased gradually from 40 to 150 × 103/μL with a decreased serum creatinine level and increased urine output, eventually allowing the withdrawal of dialysis therapy. A second kidney biopsy showed mesangial widening compatible with the healing of TMA.ConclusionsThis case indicates that aHUS with PEs and eculizumab therapy has the potential for renal recovery even if over 1 year has passed.

A case of bortezomib-associated thrombotic microangiopathy in a multiple myeloma patient

Bortezomib is a first-generation proteasome inhibitor used in the treatment of multiple myeloma. We present a case of a 70-year-old woman with multiple myeloma, who presented thrombotic microangiopathy with multi-organ involvement thrombotic microangiopathy (ocular, cardiac, and renal) after bortezomib initiation. A kidney biopsy confirmed the diagnosis of thrombotic microangiopathy. A temporal relation between bortezomib exposure and thrombotic microangiopathy onset was seen in the absence of other concurrent medication or disease known to cause thrombotic microangiopathy, and thrombotic microangiopathy was only resolved after drug discontinuation. The exact pathophysiological mechanism remains unknown. To our knowledge, this is the second biopsy-proven published case of bortezomib-associated thrombotic microangiopathy. Since bortezomib is extensively used for treating patients with multiple myeloma, prescribing clinicians should maintain a high index of suspicion of this potentially fatal complication.

Soluble C5b-9 As a Prognostic Biomarker for Thrombotic Microangiopathy at the Onset of Graft-Versus-Host Disease

Schmidt: Kypha Inc: Employment, Equity Ownership. Lee:Incyte: Research Funding; Syndax: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; AstraZeneca: Research Funding.

The Association between Transplant-Associated Thrombotic Microangiopathy and Calcineurin Inhibitor and Sirolimus Levels

Introduction: Thrombotic microangiopathy (TMA) is a known complication of allogeneic hematopoietic cell transplantation (HCT). An ongoing debate is whether TMA is caused by acute graft-versus-host disease (GVHD) or calcineurin inhibitor (CNI)/sirolimus. Previous studies have not examined the impact of CNI/sirolimus average trough levels while accounting for the confounding effect of GVHD. In the current study, we examined the association between time-varying levels of CNI/sirolimus and the onset of TMA among 2105 adult allogeneic HCT recipients.Methods: We performed a retrospective cohort analysis of allogeneic HCT recipients during 2006-2015 at Fred Hutchinson Cancer Research Center who received CNI/sirolimus for GVHD prophylaxis. TMA (outcome) was ascertained and validated as previously described (Blood 130;Suppl:666). Acute GVHD (confounder) was defined and graded according to established criteria. Consecutive CNI/sirolimus trough levels (exposure) were obtained and interval values between checks were imputed via linear interpolation. We followed patients from the time of hematopoietic cell infusion until the onset of TMA and censored patients at day 100 or >1 week of missing drug levels. To examine the association between the “type” of immunosuppressant and TMA, CNI/sirolimus exposure over time was characterized as a discrete categorical variable (tacrolimus alone, cyclosporine alone, or sirolimus + CNI). To examine the impact of the “level” of immunosuppressant on TMA, CNI/sirolimus exposure was both defined as an average of the previous 7-day trough levels (continuous variable) as well as a discrete time-above-peak variable (binary variable for tacrolimus >15 ng/mL, cyclosporine >450 ng/mL, or sirolimus >10 ng/mL). Extended Cox regression models were built to examine the time-varying association between CNI/sirolimus exposures and TMA after adjusting for GVHD.Results: In the current study, 2105 adult allogeneic HCT recipients contributed 173,171 person-days and 150 cases of TMA. The median follow-up time was 94 days and trough blood levels were checked on average 3x per week. Initial GVHD prophylaxis regimen for patients included 54% on tacrolimus (n=1135), 40% on cyclosporine (n=837), and 6% on a combination of sirolimus + CNI (n=133). Nearly no one received sirolimus alone without CNI. Eight percent of patients (n=162) had at least one switch in the immunosuppression regimen within 100 days. The median (IQR) trough levels for tacrolimus, cyclosporine, and sirolimus were 9 ng/mL (7-12), 283 ng/mL (206-372), and 5 ng/mL (4-7), respectively. Acute GVHD developed in 64% of patients including 53% grade 2 (n=1115), 9% grade 3 (n=185), 2% grade 4 (n=52).In the analysis adjusted for both discrete time-varying CNI/sirolimus exposure and GVHD, higher grades of GVHD had strong associations with TMA (Table 1: grade 2 HR 2.24, P=0.001; grade 3 HR 12.38, P<0.001; grade 4 HR 26.04, P<0.001). While cyclosporine and tacrolimus had a similar risk for TMA (HR 1.23, P=0.230), sirolimus + CNI regimen was associated with a slightly higher risk compared to CNI alone (HR 1.76, P=0.051).In the analyses of individual drug levels adjusted by GVHD, higher trough levels of tacrolimus and cyclosporine (either as a linear average level or binary time-above-peak) were not associated with an increased risk of TMA (Table 2). However, higher sirolimus trough levels were associated with an appreciable risk of TMA (HR 1.44, P=0.001 for every 1 ng/mL increase in sirolimus average trough level; HR 3.23, P=0.164 for time above 10 ng/mL).Conclusion: In allogeneic HCT patients, acute GVHD was strongly associated with the onset of TMA independent of ongoing exposures of CNI/sirolimus. We did not find an association between CNI recipients (tacrolimus versus cyclosporine) or CNI levels and the risk of TMA. However, when combined with CNI, higher sirolimus trough levels were linearly associated with a higher risk for TMA. Limitations in this observational study include the inability to adjust for concomitant medications and conditions that might have altered drug levels and inability to adjust for target drug levels since recognized risk factors might have led clinicians to target higher drug levels due to higher risks of GVHD. These findings suggest that prevention and treatment of GVHD and avoidance of high sirolimus levels will decrease the risk of TMA. DisclosuresLee:Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Onyx: Research Funding; Kadmon: Research Funding; Takeda: Research Funding. Garcia:Pfizer: Consultancy; Portola: Research Funding; Shingoi: Consultancy; Retham Technologies LLC: Consultancy; Janssen: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy; Daiichi Sankyo: Research Funding; Incyte: Research Funding; Boehringer Ingelheim: Consultancy.

Transplant-Associated Thrombotic Microangiopathy (TA-TMA): Not a Singular Entity

▪Introduction: Thrombotic microangiopathy (TMA) is a clinical syndrome that can develop after hematopoietic cell transplantation (HCT). Previous studies have been limited to small case series with conflicting results. In this large, single-center longitudinal TA-TMA database, we describe the incidence, etiology, treatment, and outcome of this rare but challenging clinical presentation.Methods: We performed a retrospective cohort analysis of consecutive allogeneic HCT recipient during 2006-2015 at Fred Hutchinson Cancer Research Center. TA-TMA was defined as persistent microangiopathic hemolytic anemia (MAHA) composed of red cell fragmentation, elevated lactate dehydrogenase (LDH), thrombocytopenia, anemia, and lack of coagulopathy (Table 1). We performed a primary search algorithm using “consecutive MAHA” followed by a secondary search algorithm using “suspected hemolysis” to identify all cases from date of transplant until date of death or last follow-up (Table 1). For each suspected case, we further reviewed available patient records to confirm the diagnosis, determine the etiology, treatment, and complication. The most likely etiology was determined by reviewing the clinical events in the 2-week window before the TMA onset. Since 96% of patients were receiving calcineurin inhibitor (CNI), we chose idiopathic/drug as a diagnosis of exclusion if all other causes were excluded. TMA resolution was defined as LDH <1.5x ULN, platelet transfusion independence, and rare or no schistocytes. Continuous and categorical variables were shown as median (interquartile range) and percentage, respectively. Overall survival was depicted with Kaplan-Meier curves, after accounting for delayed entry with left truncation at TMA diagnosis. Cox regression model was built to test the association between TMA resolution as a time-varying covariate and overall survival.Results: Among 2241 consecutive adult allogeneic HCT recipients, 209 patients (9%) met the laboratory criteria of TA-TMA (Table 2) with a median onset time of 62d (35d-93d). One hundred and nine patients (52%) had end-organ damage with either acute kidney injury (AKI) or neurologic deficit. The median follow-up was 181d (92d-478d) and 53 patients (25%) achieved hematologic resolution. Diagnostically, acute GVHD (n=96) represented the largest category and those with GVHD refractory to high dose steroid (n=61) had poor prognosis. Diffuse alveolar hemorrhage (DAH) and idiopathic pneumonia syndrome (IPS) (n=30) also frequently preceded the TMA onset. Finally, despite excluding patients with coagulopathy, non-specific causes of TMA such as disease recurrence (n=20) and systemic infection (n=33) were frequently evident.Overall survival, separated by TMA etiology is shown in Figure 1. Whereas the idiopathic/drug and non-refractory acute GVHD categories approached the survival of non-TMA post-HCT recipients, the other groups had worse prognosis. Regardless of cause, the most common treatment (32%) was CNI cessation or CNI switch (in no particular pattern). We did not observe an association between changes to CNI therapy and TMA resolution (24% vs. 26%, Fisher P 0.80) or overall survival at 6 months (37% vs. 34%, Wald P 0.75). This remained true when each diagnostic category and each CNI drug was separately analyzed. Plasma exchange was rarely performed at our center. Finally, TMA resolution often correlated with improvement of the underlying disorder. The achievement of TMA resolution was associated with significantly improved survival (HR 0.35, P <0.01).Conclusion: Despite meeting the same laboratory definition for persistent MAHA, clinical review revealed heterogeneous disease groups with dissimilar prognostic implications. Our data suggest that TA-TMA is not one disease entity but rather a “final common pathway” for several disorders that likely have different pathophysiologic mechanisms. Instead of empiric treatment with CNI adjustment, we need to identify and understand the underlying causal pathway towards TA-TMA, and to determine if earlier recognition and successful treatment improves patient outcomes. [Display omitted] DisclosuresLee:Kadmon: Other: One-time advisory board member; Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Mallinckrodt: Honoraria. Gopal:Seattle Genetics: Consultancy, Research Funding.

Use of Recombinant Thrombomodulin for Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplantation Ameliorate Disease Severity

▪Background and Objectives: Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (SCT) is a devastating complication of SCT and lacks optimal managements with a high mortality. Its pathogenesis is not well understood but suggested that endothelial toxicity caused by chemoradiotherapy, infections, immunosuppressive drugs, graft-versus-host-disease (GVHD) and infections have been thought to play important roles. Recently recombinant human soluble thrombomodulin (rTM) was reported to be a safe and efficient treatment of disseminated intravascular coagulation for hematological malignancies. rTM which contains active extracellular domain of thrombomodulin, inactivates coagulation and the thrombin-rTM complexes activates protein C to activated protein C (APC). APC in activates factors Va and VIIIa with protein S, and subsequently lead to further thrombin formation. And, also rTM possesses cytoprotective effects against calcineurin inhibitor induced endothelial cell damage, anti-inflammatory activity such as decrease of high-mobility group box 1 protein, IL-6 and TNF-a. Hence we compared the efficacy of rTM with TMA to other conventional treatments.Patients and Methods: Of 223 patients who had received SCT in our institute from January 2009 to March 2014, 16 patients diagnosed as TMA after allogeneic stem cell transplantation were identified from database. Diagnosis of TMA was based on the Bone Marrow Transplant Clinical Trials Network (BMT-CTN). Patients treated with rTM as a first-line therapy were categorized as rTM group and treated with other therapies as a first-line therapy were as control group.Results: TMA occurrence was total 16 cases (7.2%). rTM group had 9 patients and control group had 7 patients. rTM group had male dominant (M/F 8/1 vs. 1/6) compared to control group. Both group showed similar age, disease distribution (rTM; 2 Leukemia, 5 Lymphoma and 2 ATLL vs. control; 3 Leukemia, 2 CML-BC and 2 ML), disease risk (rTM; 2 standard (1-2 CR or MDS) and 7 high vs. control; 7 high), hematopoietic cell transplantation specific comorbidity index, type of donor source (rTM; 5 related PBSC and 4 unrelated BM vs. control; 4 related PBSC and 3 unrelated BM), HLA compatibility (rTM; 4 haplo-identical donor vs. control; 3 haplo), conditioning regimen (rTM; 8 reduced intensity vs. control; 5 reduced intensity), GVHD prophylaxis (rTM; 5 CyA/Tac and short MTX, 4 Tac/ATGmPSL vs. control; 5 CyA/Tac and short MTX, 2 Tac/ATGmPSL) and year of transplant. Median onset of TMA in rTM group and control group were on day 24.5 (16-274) and day 72 (7-338) (p=0.13) post SCT, respectively. Compared with control group, rTM group revealed significantly superior overall survival after the onset of TMA (Figure1, p=0.043). Seven patients (77.8%) of rTM group recovered from TMA, while no patients recovered in control group. Acute GVHD were occurred in 5 cases of rTM group and in 4 cases of control group (p=0.29). Grade II to IV acute GVHD were occurred in 3 of rTM group and in 4 cases of control groups (Figure 2, P=0.66). Leading causes of death were 4 GVHD of 5 cases in rTM group and 3 TMA of 7 cases in control group. Both group had no lethal hemorrhagic event.Conclusion; The use of rTM in TMA improved overall survival after the onset of TMA in this retrospective small number analysis. rTM reduced TMA mortality but GVHD was still a major cause of death in TMA survivors. Larger prospective studies are warranted to fully evaluate the efficacy of rTM. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Serial Profile of Vitamins and Mineral Microelements During the Acute Phase of Hematopoietic Stem Cell Transplantation.

Abstract 3033In hematopoietic stem cell transplantation (HSCT), oral intake is severely impaired by preparative regimen-induced mucosal toxicity and nausea. Therefore, parenteral nutrition (PN) is usually administered. The vitamin preparation accompanying PN therapy is based on the FDA recommendation proposed in 2000. However, it remains unknown whether this preparation retains adequateness for HSCT recipients who undergo strenuous conditioning regimens and immunological reactions, which put them in a hyper catabolic state. Additionally, almost no study has been conducted to examine the relevance of standard regimen of mineral microelements supplementation during HSCT.In this prospective observational study, we measured the blood level of selected vitamins (vitamin B1, B6, C, K, E, and folate) and mineral microelements (iron, zinc, copper, and selenium) during the peri-HSCT period (measured weekly from 1 week before until 4 weeks after HSCT). Oral and parenteral total energy amounts, administration of multivitamin preparation, and mineral supplementation, were recorded. The subjects were 15 adult patients who received allogeneic HSCT for hematological malignancies (AML: 7, ALL: 1, CML: 1, MPN: 2, MDS: 2, NHL: 2) at The University of Tokyo Hospital. Eight of them received CY/TBI-based full conditioning and the others received fludarabine-based reduced intensity regimens. All the patients received PN with vitamin and mineral preparations when their oral intake decreased to less than 700 Kcal/day. PN was modified adequately in case of organ dysfunctions. Engraftment was observed in all but one patient, and one died before day 28 due to sepsis. The most striking finding was the marked deficiency of vitamin C, a major antioxidant vitamin. Vitamin C levels dropped just after conditioning regimens started, and reached a nadir (2.1+-1.49 microgram/mL, normal range: 5.5–16.8) at day 14. The deficiency levels at day 7 and day 14 were significantly correlated with increase of acute phase inflammatory proteins (p=0.03 for C-reactive protein and p=0.004 for ferritin, at day 7), which suggests that the current vitamin C complement regimen is insufficient for patients who suffer from intense inflammation. On the other hand, vitamin E, another antioxidant vitamin, remained within the normal level during the surveillance period. Selenium is a microelement that assists antioxidative effect and has attracted attention because emerging evidence suggests its relevance for critically ill condition. Although it is not contained in the standard PN preparations, our results indicated no sign of shortage. Selenium is abundant in normal diet, and short suspension of oral intake does not induce selenium depletion. Marked excess of vitamin K was another point of note. The average vitamin K level continued to rise after the start of the conditioning regimen, and exceeded 10 times of the normal upper level (0.15 – 1.25 ng/mL) at day14 (12.8 +- 5.6 ng/mL), day 21 (17.4 +- 17.9), and day 28 (12.1+- 25.0). These abnormal rises were observed especially in patients with prolonged administration of PN, suggesting overdosing of vitamin K in the standard vitamin preparations. Vitamin K excess would be problematic because it causes hypercoagulability; however, it was not clinically correlated with the onset of thrombotic microangiopathy in our cohort. Vitamin B1 was slightly but significantly below the normal lower limit. Its deficiency started before the conditioning regimen and persisted through day14. Considering increased requirement of vitamin B1 during a debilitating state, this shortage should be corrected with active supplementation before the patients undergo a stressful conditioning process. Other substances (folate, zinc, iron, and copper) remained almost within a normal range.In conclusion, the nourishment status during peri-HSCT period is characterized by marked depletion of vitamin C and excess of vitamin K, and other aberrations with less degree of deviation. These results indicate that normal PN is not adequate for HSCT patients. Development of vitamin and microelement preparation that is optimized for HSCT setting should be discussed. Disclosures:Nannya:Otsuka Seiyaku Koujyou: Research Funding.

Thrombotic Microangiopathy Associated with Sirolimus Level after Allogeneic Hematopoietic Cell Transplantation with Tacrolimus/Sirolimus-Based Graft-versus-Host Disease Prophylaxis

Posttransplantation thrombotic microangiopathy (TMA) is a multifactorial complication of allogeneic hematopoietic cell transplantation (allo-HCT) whose incidence is increased with the use of a sirolimus plus tacrolimus (SIR/TAC) regimen for acute graft-versus-host disease (aGVHD) prophylaxis. We evaluated the incidence and possible risk factors for TMA in a case series of 177 patients who received allo-HCT using SIR/TAC-based GVHD prophylaxis. The patients received either a sibling donor graft (n = 82) or a matched unrelated donor graft (n = 95). Within the first 100 days post-HCT, 30 patients (17%) were diagnosed with TMA, and an additional 9 patients (5%) were classified as probable TMA cases. The median time to onset of TMA was 4.6 weeks (range, 1.6-10.6 weeks). Thirty-four patients developed both TMA and aGVHD, with the majority (81%) developing aGVHD first. Multivariate analysis identified the following factors as associated with increased risk of TMA: day 14 serum sirolimus level ≥9.9 ng/mL (hazard ratio [HR], 2.19; 95% confidence interval [CI], 1.13-4.27; P = .02), presence of previous aGVHD grade II-IV (HR, 3.04; 95% CI, 1.38-6.71; P < .01), and fully myeloablative conditioning (HR, 3.47; 95% CI, 1.60-7.53; P < .01). These risk factors for TMA suggest that when using a SIR/TAC regimen for GVHD prophylaxis, careful monitoring and adjustment of the sirolimus dosage is critical, particularly in patients with active aGVHD.

Treatment of atypical uraemic syndrome in the era of eculizumab.

Treatment of atypical uraemic syndrome in the era of eculizumab.

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.

Decreased ADAMTS13 Levels in Patients after Living Donor Liver Transplantation

Introduction Thrombotic microangiopathy (TMA) is a complication occurring after liver transplantation (LT), and an unusually large multimer (ULM) of Von Willebrand factor (VWF) and ADAMTS13 may play an important role in the onset of TMA during LT. Material and Methods Eight-one patients underwent living donor LT (LDLT). Seventeen of those patients had both severe thrombocytopenia and hemolytic anemia with fragmented red cells and were diagnosed as TMA- like syndrome (TMALS). Results and Conclusions A significant reduction of ADAMTS13 and an increase of VWF were observed in the patients with TMALS. The ADAMTS13 activity in patients after LDLT was significantly reduced from day 1 to day 21, and it was significantly low in those with TMALS at day 14 and 28. The VWF levels in patients with LDLT were significantly high, and the VWF/ADAMTS13 ratio was significantly increased in patients at 7, 14 and 28 days after LDLT, especially in patients with TMALS at day 14 and 28 after LDLT. High molecular weight multimers of VWF were observed to have increased in patients with LDLT, and the high molecular weight multimers of VWF were further increased in those with mild TMALS but they decreased in those with severe TMA. These findings suggest that ULM- VWF and ADAMTS13 might be associated with the onset of TMA after LT.

Thrombotic Microangiopathy with Tacrolimus/Sirolimus-Based GVHD Prophylaxis Regimen in Patients Undergoing Hematopoietic Stem Cell Transplant from a Matched Unrelated Donor

Thrombotic microangiopathy (TMA) is a multifactorial complication of related and unrelated allogeneic hematopoietic stem cell transplant (allo-HSCT). The true incidence of TMA is difficult to estimate due to lack of agreement on a single definition. Diagnosis is often complicated by multiple potential etiologies for the clinical findings. Sirolimus (SIR), an inhibitor of mammalian target of Rapamycin (mTOR), is a novel immunosuppressive agent that works synergistically with calcineurin inhibitors (CNI) to prevent graft-versus-host disease (GVHD) in allo-HSCT. Recently, the addition of SIR to CNIs was reported to result in a higher than expected incidence (10.8%) of TMA (Cutler et al. BBMT 2005; 11:551–7). We evaluated the incidence and risk factors for TMA in a cohort of patients undergoing matched unrelated (MUD) HSCT using SIR combined with tacrolimus (TAC) and mini-methotrexate for GVHD prophylaxis at City of Hope. TMA was defined as SCr increase of ≥ 50% above baseline, LDH twice the institutional upper normal limit, presence of schistocytes or persistent presence of nucleated red blood cells, and prolonged or progressive thrombocytopenia (platelets <50 × 109/L or ≥ 50% decrease from previous count). A case series of 47 MUD-HSCT patients were included in this retrospective chart review study. The median age was 50 years (range: 19–67); (male/female: 28/19). Conditioning regimens consisted of fludarabine/melphalan (65%) and FTBI combined with cyclophosphamide or etoposide (35%). Diagnoses included ALL (32%), AML (25%), NHL (15%), MDS (15%), MPD (9%), CML (2%), CLL (2%). Twenty-six patients (55%) had a 10/10 matched (HLA-A, B, C, DRB1, and DQB1) donor by high-resolution on typing. The median follow up for the 30 surviving patients is 14.5 months (2.8–26). The one-year probabilities of overall survival and non-relapse mortality (NRM) were 61% and 19%, respectively. Grade II-IV acute GVHD (aGVHD) was reported in 60% of all patients (grade III-IV: 25%). Thirteen (28%) patients met the above diagnostic criteria for TMA. In addition, we included two patients who did not meet the criteria due to missing tests but were clinically diagnosed with TMA by independent attending physicians, resulting in the total incidence of 32% (15/47). Four of the 15 patients met the criteria for TMA as a result of ongoing multi-organ failure secondary to other causes. The median time to TMA onset was five weeks (2–20 weeks). Most cases (93%) occurred within the first 100 days post-HSCT. Thirteen patients developed both TMA and aGVHD, in which the majority of patients (70%) developed TMA after a diagnosis of aGVHD had been made. Initial treatments for TMA included holding TAC (33%), holding SIR (20%), holding or adjusting doses (27% and 20%, respectively) for both drugs. One patient underwent plasma exchange. Sixty percent of patients subsequently recovered from TMA as defined by normalization of laboratory values. Of the 17 expired patients, ten were diagnosed with TMA. Causes of death were as follows: for TMA cases, relapse mortality=3, NRM=7; for Non-TMA patients, relapse mortality=6, NRM=1. At the time of TMA diagnosis, the median TAC and SIR levels were 11.3 (0–18.8) and 7 (0–23.9) ng/ml, respectively, in contrast to the median TAC and SIR levels for non-TMA patients at 6.1 (p= 0.02) and 5.5 (p=0.13) ng/ml, respectively. To identify other possible risk factors for TMA, the following patient and treatment-related characteristics were examined: age, conditioning regimen, disease type, degree of HLA match, and exposure to triazole antifungals. Only higher tacrolimus levels (HR: 6.9, p<0.01) and aGVHD grades III-IV (HR: 3.5, p=0.02) were associated with an increased risk for TMA. In conclusion, TMA is common after MUD allo-HSCT using SIR-containing GVHD prophylaxis. The risk factors for TMA suggest that careful monitoring and adjustment of TAC/SIR dosages to avoid super-therapeutic levels is critical, particularly during ongoing GVHD.

Thrombotic Microangiopathy due to Malignant Hypertension Following Corticosteroid Therapy for Microscopic Polyangitis

A 78-year-old woman was treated with 40 mg of prednisolone for microscopic polyangitis, and favorable effects were observed. However, her blood pressure increased and she developed severe thrombocytopenia. Thrombotic microangiopathy (TMA) due to malignant hypertension was suspected and she was treated with an angiotensin-converting enzyme inhibitor; her platelet count then rose. She showed a close temporal relationship between initiation of corticosteroid therapy and the onset of TMA. Corticosteroid therapy should be used with caution in patients with underlying vascular endothelial damage.

Preferential Th2 Polarization at the Onset of Thrombotic Microangiopathy (TMA): Immunological Comparison of TMA Versus Acute GVHD in Terms of Peripheral T Cell Subsets, Dendritic Cell Subsets and Cytokine Profiles.

Thrombotic microangiopathy (TMA) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a serious complication with a high mortality. Acute GVHD (aGVHD) is one of risk factors for TMA and often overlaps it. In particular, gastrointestinal endothelium is a common target of aGVHD and TMA, which makes clinical diagnosis of TMA difficult, leading to delay early and appropriate treatment for it. In this study, to gain more insight into differences between TMA and aGVHD, comprehensive immunological analysis was performed.Methods: We determined kinetics of peripheral T cell subsets (CD4, CD8, Th1, Th2, γδ-T, NKT) and dendritic cell (DC) subsets (CD11c+DC and CD123+DC), serum 17 different cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, TNF-α, IFN-γ, G-CSF, GM-CSF, MIP-1β, MCP-1), and C-reactive protein (CRP) at the onsets of aGVHD or TMA in 25 patients undergoing allo-HSCT. T cell subsets including CD4 (CD3+CD4+CD8−), CD8 (CD3+CD4−CD8+), Th1 (CD4+CXCR3+CCR4−), Th2 (CD4+CXCR3−CCR4+), γδ-T (CD3+TCR-Vδ2+), and NKT (CD3+CD161+) and DC subsets were determined with a flow cytometer. TMA was diagnosed, following Iacopino's criteria (Iacopino et al, Bone Marrow Tranplant. 24: 47, 1999). Data of aGVHD or TMA were compared with those of control without either aGVHD nor TMA between on 30 days and 60 days after allo-HSCT.Results: There was a significant decrease in the percentage of Th1 cells in CD4+T cells in TMA (9.1%, n=10), compared to in aGVHD (24.9%, n=9, p=0.003) or in control (21.6%, n=12, p=0.009). In contrast, the percentage of Th2 cells in CD4+T cells was higher in TMA (20.2%) than in aGVHD (9.3%, p<0.001) or in control (12.1%, p=0.003). Accordingly, a significant increase in Th2/Th1 ratio was observed in TMA (4.0), compared to in aGVHD (0.4, p<0.001) or in control (0.7, p<0.001). In addition, a significant increase in the percentage of CD4 cells in CD3+T cells in TMA (59.2%, n=9) was found, compared to in aGVHD (31.2%, n=8, p=0.005) or in control (34.8%, n=11, p=0.007). The percentage of CD8+ cells in CD3+T cells was lower in TMA (26.3%) than in aGVHD (45.8%, p=0.03) or in control (54.4%, p=0.002). On the other hand, there was a significant increase in the ratio of CD11c+DC/CD123+DC in aGVHD (3.6, n=8), compared to in TMA (1.4, n=5, p=0.02) or in control (n=1.8, p=0.02). γδ-T and NKT did not show any significant changes among aGVHD, TMA and control. Moreover, no significant changes were observed in either 17 different cytokines among aGVHD, TMA and control. Of note, in TMA but not in aGVHD nor in control, positive correlations of Th2/Th1 ratio were found with IL-6 (p=0.01, r=0.91, n=6), IL-10 (p=0.03, r=0.86, n=6), and CRP (p<0.001, r=0.93, n=9).Conclusion: Preferential Th2 and CD4 polarizations were observed at the onset of TMA. Thus, simultaneous monitoring of Th1, Th2, CD4 and CD8 was suggested to become a useful immunological parameter for differentiating TMA from aGVHD after allo-HSCT.