Incidence Of Thrombotic Microangiopathy Research Articles

MO175: Association between Thrombotic Microangiopathy, ADAMTS13 Activity and Development of AKI, ARDS, AND Poor Outcomes in COVID-19 Patients (Pilot Study)

BACKGROUND AND AIMSCases of microangiopathy associated with COVID-19 are not fully understood. We aimed to clarify in these patients the presence of thrombotic microangiopathy (TMA) and decreased ADAMTS13 activity, the possible influence of these factors on kidney and lung damage, and outcomes.METHODThe study involved 90 patients with COVID-19 and viral pneumonia, who were treated at the Pavlov First St. Petersburg State Medical University. Patients undergoing plasma transfusion were excluded. In addition to the standard examination, activity of ADAMTS13 was determined in admission (ELISA, normal range 30–160%).RESULTSMedian level ADAMTS13 was 92%, IQR 27.9%. The presence of TMA took place in 26.7% of patients, in 41.5% patients with TMA the level of activity of ADAMTS13 was less than 60%. In patients with respiratory failure, the ADAMTS13 level was significantly lower–78.4%, IQR 32.1% versus 108.6%, IQR 26.7%. In patients with respiratory failure (P < .01), the incidence of TMA was significantly higher–34.2% versus 19.3%, respectively (P < .01). The ADAMTS13 level neg. correlated with the risk of developing TMA (ρ = –0.486, P < .01), AKI of any stage (KDIGO2012 criteria) (ρ = –0.288, P < .01), acute respiratory distress syndrome (ARDS, ‘Berlin definition’) (ρ = –0.304, P < .01), the duration of hospitalization (ρ = –0.342, P < .01) and the probability of death (ρ =–0.278, P < .01). In the case of five patients, an extremely low level of ADAMTS13 (less than 30%) was noted, which in all cases was accompanied by laboratory signs of TMA and the development of ARDS; two patients had a fatal outcome.CONCLUSIONTMA and low ADAMTS13 activity are associated with progression to severe COVID-19 disease and development of AKI. Some of the cases of TMA in these patients may be due to low ADAMTS13 activity. Further research is needed to assess the potency of treating these patients with TMA associated with low ADAMTS activity.

Carfilzomib-induced thrombotic microangiopathy is underestimated in clinical practice: A report of five patients and literature review

Carfilzomib (Cfz) is widely used to treat multiple myeloma. However, real-world data of the incidence of thrombotic microangiopathy (TMA) caused by Cfz is inconsistent (<1–5%). We evaluated 96 consecutive patients who received Cfz to evaluate the incidence of TMA in clinical practice. TMA developed in five patients (5.2%) who were mainly receiving high-dose Cfz (≥56 mg/m2). Based on a literature review, precaution should be taken for Cfz-induced TMA in male patients receiving high-dose Cfz irrespective of the combination therapy, Cfz administration period, and complement level. In conclusion, Cfz-induced TMA might be underestimated in clinical practice, and early intervention should be considered.

Influenza-induced thrombotic microangiopathy in a patient with cancer on proteasome inhibitor: a diagnostic dilemma.

Thrombotic microangiopathy (TMA) in a cancer patient is a common complication of either cancer itself or anticancer therapy. Incidence of TMA from anticancer therapy was found to be > 15%, since the introduction of anti-angiogenic drugs like anti-vascular endothelial growth factor agents. It is, however, important to not ignore other causes of TMA such as bacteria, viruses, antiplatelet drugs, hereditary complement mutations, and autoimmune disorders. We present such a diagnostic dilemma in our patient who was admitted with influenza and was found to have TMA on renal biopsy, while on proteasome inhibitor (PI) therapy. With this case, we would like to highlight the importance of understanding the true cause of TMA to avoid unwarranted long-term discontinuation of life saving anti-cancer drugs after TMA resolution.

Carfilzomib Is Safe in Elderly Patients with Multiple Myeloma but Thrombotic Microangiopathy Is Underestimated in Clinical Practice

IntroductionCarfilzomib (K or Cfz) is a widely used second-generation proteasome inhibitor for patients with multiple myeloma (MM). However, despite the numerous positive clinical results, there were only a few “real-world” studies, particularly among elderly patients. Avoiding Cfz for the elderly may be based on a potential selection bias to avoid rare but serious cardiovascular adverse events (CVAEs) associated with Cfz. Moreover, although Cfz-associated thrombotic microangiopathy (TMA) has been recently recognized, the incidence rate of TMA varied from less than 1% to 5.0%. To determine the efficacy of Cfz and occurrence of CVAEs in the elderly patients and the incidence of TMA, we reviewed 96 patients, including 28 elderly patients (aged ≥76 years) at our center. All participants or their family members provided written informed consent for inclusion in the study. The study was conducted according to the Declaration of Helsinki and approved by the ethical review board of our institute.MethodsCfz was administered in the same protocol as in each clinical trial. The choice of the Cfz regimen and the criteria for dose reduction, including dexamethasone use, were based on the patient's background and discretion of the treating physician.Severe CVAEs were defined as events of grade ≥3 including heart failure, acute coronary syndrome, relative reduction in the left ventricular ejection fraction ≥20% from baseline, QT prolongation (corrected QT: ≥501 ms), and hypertension (systolic blood pressure of ≥160 mm Hg and/or diastolic blood pressure of ≥100 mm Hg, requiring two or more additional intensive medications than before) that were observed within three months after the initiation of Cfz therapy. The diagnosis of TMA was made as follows: when clinical findings were consistent with microangiopathic hemolytic anemia, such as thrombocytopenia, progressive anemia with schistocytes, elevated lactate dehydrogenase, and other differential diseases, including bacteremia or tumor progression, could be excluded.ResultsThe patients' median age at Cfz initiation was 71 (range, 30-91) years. In total, 96 (100%), 86 (89.6%), 22 (22.9%), and 23 (23.9%) patients received bortezomib, lenalidomide, daratumumab, and autologous stem cell transplantation before Cfz therapy.Until the end of the study, 13 CVAEs (13.5%) of grade ≥3 were observed, including 2 (11.1%), 1 (11.1%), and 10 (15.2%) in patients who received Kd (Cfz and dexamethasone), DKd (Daratumumab, Cfz, and dexamethasone), and KRd (Cfz, lenalidomide, and dexamethasone), respectively. Despite the use of appropriate supportive care, grade ≥3 AEs resulting in Cfz withdrawal were noted in 25 patients: CVAEs in 11, thrombocytopenia in 4, TMA in 3, and infection in two patients. Notably, one patient with end-stage myeloma who received KRd 20/27 mg/m 2 died of CVAE on day 10 of cycle 1.At Cfz initiation, 28 patients were aged 76-80 (n=14) and ≥81 years (n=14) (Fig. 1). Three elderly patients had severe CVAEs (10.7%). The median numbers of prior chemotherapy to Cfz, time to next treatment, and overall survival from Cfz initiation were 2.5, 28.0, and 41.1 months, respectively. Although 10 patients (35.7%) discontinued Cfz therapy due to disease progression, only four patients (14.3%) discontinued Cfz owing to grade ≥3 AEs, including TMA (n = 1) and CVAEs (n = 3).Overall, five patients (5.2%) showed TMA. All patients received Kd-based regimens upon TMA development (Kd, n = 2 and DKd, n = 3). The median age of the patients who developed TMA was 74 years, and the Cfz dose was 20/27 in 1, 20/36 in 1, and 20/56 mg/m 2 in three patients. Although three patients developed TMA during the first Cfz cycle (on days 11, 16, and 21, respectively), two patients received KRd therapy before the Kd therapy that caused TMA. Two patients required temporary dialysis and four patients discontinued Cfz therapy. Eculizumab was administered in a patient and a kidney biopsy showed that the lumen of most glomerular capillaries was occluded by fibrin thrombi (Fig. 1). Furthermore, the vessel in the vascular pole of the glomerulus had necrotic lesions, suggesting drug-induced and complement-mediated TMA.ConclusionCfz could be used safely in the elderly patients. The incidence of CVAEs by Cfz in elderly patients was similar to that in the entire cohort. The incidence of TMA was 5.2%, and Cfz-induced TMA should be carefully considered, particularly in patients using high-dose Cfz. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Utilizing Organ-Sparing Marrow Irradiation to Condition Patients Prior to Allogeneic Hematopoietic Cell Transplant with High-Risk Hematologic Malignancies: Results of a Pilot Study

Background: Total body irradiation (TBI) has long been incorporated as part of the conditioning regimen prior to hematopoietic stem cell transplant (HSCT). While the myeloablative TBI conditioning is associated with a lower relapse rate in high risk diseases such as Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Acute Lymphoblastic Leukemia (ALL), it is also associated with substantial toxicities, and increased NRM so use of this regimen is limited to young patients with excellent performance status. In this study, we used a linac-based volumetric modulated arc therapy (VMAT) technique to deliver standard myeloablative radiation to high risk body sites while sparing radiation sensitive organs (Organ Sparing Marrow Targeted Irradiation, OSMI). We hypothesized that this technique would be feasible and safe in patients who are older or who have higher transplant specific comorbidity index (HCT-CI), typically ineligible for standard TBI conditioning.Methods: This is a single-arm prospective study. Patients from age 18-75 with high risk AML, MDS or ALL were eligible. There are 3 cohorts: (1) age 18-50 with HCT-CI of 3/4; (2) age 51-65 with HCT-CI of ≤ 3; and (3) age 66-75 with HCT-CI of ≤ 2. Patients receive OSMI to a total dose of 1200 cGy delivered twice daily for 6 fractions for a total of 7200 cGy. Clinical tumor volume includes total skeletal bone marrow and any sanctuary or high-risk areas. Graft-versus-host disease (GVHD) prophylaxis originally was tacrolimus and methotrexate. Given high incidence of bacterial infections related to mucositis, prophylaxis was changed to tacrolimus and sirolimus without methotrexate. All patients received Keratinocyte growth factor for prevention of mucositis. The primary objective was to assess feasibility and tolerability of OSMI based HSCT as defined by transplant-related mortality (TRM) at day 30 (D30) as well as rate of grade II/III organ toxicity (defined by Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days.Results: Patient demographics for the 24 patients are shown in Table 1. Median age of recipients was 56.5 years. No graft failures were observed. The most common grade II or III Bearman toxicities include mucositis (grade 2: n=4), and diarrhea (grade 2: n=4). Clinical outcomes are shown in Figure 2. With a median follow-up of 3.3 years, overall survival (OS) and relapse-free survival (RFS) at 2 years was 78% and 74% respectively. Among the 5 patients who were not in complete remission at the time of transplant, 2-year OS and RFS rate was 40%. Incidence of Grades II-IV acute GVHD was 79% and Grades III-IV GVHD was 30%. Relapse incidence was 4% at 2 years. Incidence of Thrombotic microangiopathy by day 100 (TMA) as defined by Jodele's criteria was 17%. Incidence of chronic GVHD was 45% and severe chronic GVHD was 16%. One year non-relapse mortality was 22%, likely due to higher incidence of GVHD.Conclusions: Selected patients who are older or with higher HCT-CI, who are typically not candidates for standard TBI conditioning, were able to receive a radiation-based myeloablative conditioning regimen with 2 year overall survival rates of 78%. We observed a high incidence of TMA, possibly related to use of tacrolimus and sirolimus as GVHD prophylaxis, and a high incidence of Grade II-IV acute GVHD. Low incidence of relapse was observed. OSMI-based conditioning was feasible in this cohort with median age of 56 years and was associated with low rates of relapse and favorable 2 year overall survival. [Display omitted] DisclosuresVasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Jaglowski: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. de Lima: Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding.

Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection: a retrospective analysis of a single center.

This study aimed toevaluate the feasibility and clinical effect of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for the treatment of pediatric patients with chronic active Epstein-Barr virus infection (CAEBV). Children with CAEBV who did not have matched donors and underwent haplo-HSCT in Beijing Children's Hospital, Capital Medical University, from October 2016 to June 2020 were analyzed retrospectively. Data relating to the clinical manifestations, engraftment, and prognosis of the children were extracted from medical records. Twenty-five patients, including 16 males and 9 females, with an onset age of 5.0 ± 2.6years and a transplantation age of 6.9 ± 2.9years, were enrolled in this study. The mean time from diagnosis to transplantation was 3.8 (2.0-40.2) months. The mean observation time was 19.0 ± 12.0months. Three patients received the reduced intensity conditioning regimen, and the remaining patients all received the modified myeloablative conditioning regimen. By the end of the follow-up, 23 patients were characterized by disease-free survival (DFS), 22 were characterized by event-free survival (EFS), and two died. One of the patients died of thrombotic microangiopathy (TMA), and another died of graft versus host disease (GVHD); this patient discontinuedthetreatment for economic reasons. The 3-year overall survival (OS) rate was estimated to be 92.0% ± 5.4%, and the 3-year EFS rate was estimated to be 87.4% ± 6.8%. All active patients survived after HSCT event-free. Acute GVHD degrees 1-3 were observed in ten patients (40.0%), and degree IV was observed in six (24.0%), who were all cured except for one patient. Chronic GVHD was observed in nine (36.0%), and most of these cases were mild. The incidence of TMA and veno-occlusive disease (VOD) was 28.0% and 4.0%. Haploidentical hematopoietic stem cell transplantation is safe and effective in the treatment of pediatric CAEBV and can be used as an alternative therapy without matched donors or emergency transplantation. Patients with active disease before HSCT also benefited from haplo-HSCT. Haplo-HSCT requires careful monitoring for complications, such as GVHD and TMA. Early detection of TMA and timely treatment can reduce mortality and can improve the survival rate.

Thrombotic microangiopathy after kidney transplantation: causes, clinical specifics and outcomes

Background: Thrombotic microangiopathy (TMA) is a clinical and morphological phenomenon characterized by specific microvascular injury, microangiopathic hemolytic anemia, and damage of various target organs. TMA after kidney transplantation (post-renal transplant TMA) is a serious complication affecting the recipient and graft survival.Aim: To analyze the timing, causes, specifics of the clinical course and outcomes of TMA in renal transplant recipients.Materials and methods: This one-center study was based on a comprehensive examination and follow-up of 697 patients who had undergone 728 kidney transplantations (KT) from deceased donors in 2003–2019. Post-transplant TMA of the renal graft was confirmed morphologically in all cases.Results: We identified 32 episodes of post-transplant TMA in 32 patients; thus, the incidence of TMA was 4.4%. All cases developed after KT de novo; no recurrent TMA was observed. TMA was systemic in 37.5% and locally renal in 62.5% of the patients. The median time to the development of post-transplant TMA was 0.55 (range, 0.1 to 51.6) months. The patients with TMA did not differ from those without by gender, age, body mass index, underlying disorders, type and duration of dialysis before KT, protocols of immunosuppressive therapy, incidence of surgical, urological, infectious, cardiovascular and oncological complications. The patients with TMA were significantly more likely to have graft rejection (25.0% vs 11.2%, p = 0.035) and a never-functioning transplant (28.1% vs 4.9%, p &lt; 0.001). The presence of TMA negatively affected the transplantation outcomes. The cumulative 1-year graft survival in the patients without and with TMA was 91% and 44%, respectively, whereas their 5-year survival rates were 68% and 25% (p &lt; 0.001). The leading causes of TMA were: donor pathology (31.2%), antibody-mediated rejection (28.1%), and cyclosporine/tacrolimus nephrotoxicity (21.9%); the proportion of other causes was 18.8%. A combination of TMA etiological factors was identified in 68.7% of the recipients. The recipients with of calcineurin inhibitors nephrotoxicity had a more favorable prognosis compared to those with other causes of TMA.Conclusion: Post-renal transplant TMA is an infrequent but serious complication that worsens the graft survival and often is life-threatening for recipients. In most cases, TMA develops in the early post-operative period; however, it can occur any time thereafter. To improve the outcome of TMA, early diagnosis is necessary based on clinical suspicion and a prompt biopsy of the renal graft with suspected TMA. Treatment should be started quickly with consideration of the cause of the complication.

CD40 Ligand Levels in Pediatric Cohorts Correlate with Baseline Platelet Count and Transplant-Associated Mortality but Not with Endothelial Injury

Introduction CD40 ligand (CD40L), primarily expressed on activated CD4+ T lymphocytes, is also secreted in soluble form by T cells and platelets. CD40L modulates the immune response, largely via binding to CD40 on B lymphocytes. CD40L is also expressed on endothelial cells and with CD40 regulates endothelial cell integrity and vascular inflammation. Recently, it has been reported that single nucleotide polymorphisms (SNPs) in the CD40LG gene are associated with increased risk of endothelial complications following allogeneic stem cell transplantation (Rachakonda et al JCO 36(8)789-800). We hypothesized that incidence of thrombotic microangiopathy (TMA), a severe endothelial complication, would be associated with protein levels of CD40L early after transplant. Methods We analyzed serum collected prospectively from two cohorts of pediatric HSCT patients at their pre-transplant baseline. Serum was analyzed at day + 14 after transplant for cohort 1. CD40L levels were measured via R&D Quantikine ELISA. Genotyping of the previously reported SNPs (rs3092920 rs3092952 and rs3092936) was performed for cohort 1 using Applied Biosystems TaqMan technology. Results Initial analysis of cohort 1 revealed that patients with bone marrow failure syndromes had dramatically decreased CD40L levels as compared to other diagnoses, likely due to underlying cytopenias (Figure 1). These patients were excluded from further analysis due and a total of 125 patients were then analyzed across two cohorts. Associations between baseline CD40L levels and outcome are shown in Table 1. There is no significant correlation between CD40 level and TMA or GVHD. Cohort 1 also showed no correlation between CD40L level and GVHD or TMA at day +14. Interestingly, in both cohorts there is a significant association between post-transplant mortality and low baseline CD40L levels. This finding is independent of the indication for transplantation. CD40L is produced by platelets and platelet counts correlated with CD40L level at baseline. Mortality was increased in those with lower pre-transplant platelet counts. There was no association between genotype at the assessed SNPs and baseline CD40L levels or mortality (Table 2). No association was seen with genotype and day +14 CD40L levels. Conclusion CD40L levels prior to HSCT and at day +14 (when endothelial injury occurs) do not correlate with the risk of developing TMA. Levels of CD40L do not correlate with genotype at three SNPs either, including rs3092936 where the CC/CT genotype has been reported to increase risk of TMA and death. However, lower baseline levels of CD40L are associated with risk for post-transplant mortality, independent of diagnosis. Additionally, they correlate with baseline platelet count. We hypothesize that CD40L levels serve as a surrogate for platelet count and that baseline platelet count itself may predict risk for transplant related mortality.

Abstract 553: High-Intensity Interval Training Partly Restores Thrombotic Microangiopathy in an Experimental Model of Hypertensive Renal Injury

To investigate whether high intensity interval training can reduce hypertensive renal injury in Dahl salt-sensitive rats. Adult females Dahl salt-sensitivity (Dahl SS) rats were randomized in three groups: sedentary low-salt diet (LS, N=20: 0.3% NaCl), sedentary high-salt diet (HS, N=40: 8% NaCl) or high-salt diet submitted to high intensity interval training (HIT, N=20: 8% NaCl + HIT, 3x38 min/wk; 60% HRmax adding 4 intervals of 4 min at 90% HRmax). After 30 weeks of follow-up, 24h urine has been collected in metabolic cages, followed by tissue harvesting. HIT did not affect the development of hypertension induced by high-salt intake in the Dahl SS rats (147±55 vs 209±80* vs 203±79* mm Hg, for LS, HS and HIT, respectively; *p&lt;0,05 compared to LS). However, total mortality was significantly reduced (p=0.0022) in the HIT group (8/20 events) compared to HS (23/40 events) and LS (1/20 events) groups (94.7% vs 39.9% vs 59% survival, for LS, HS and HIT respectively), most of the deaths caused by stroke (69.6% incidence in HS rats). Chronic high blood pressure caused microalbuminuria that was not reverted by exercise (0.65±0.34 vs 95±42* vs 72±37* mg/24h, for LS, HS and HIT, respectively; *p&lt;0.05 compared to LH). Creatinine clearance was not changed by either hypertension or exercise (1.91±0.58 vs 1.73±0.85 vs 1.60±0.66 ml/min, for LS, HS and HIT, respectively; p=0.53). Histological analysis of the renal injury reveled that HIT did not reverse the expansion of mesangial matrix (125±40 vs 179±44* vs 188±47*, for LS, HS and HIT, respectively; *p&lt;0.05 compared to LS) and no glomerulosclerosis were detected (69±36 vs 97±36 vs 117±57, for LS, HS and HIT, respectively; p=0.12). Interesting, HIT significantly reduced (7/10) the number of nephrons with thrombotic microangiopathy observed in the HS (10/11) compared to LS (0/15) group (0.00±0.00 vs 8.82±2.82* vs 6.60±3.06 counts/kidney, for LS, HS and HIT, respectively; *p&lt;0.05 compared to LS). Taken together our data demonstrate that, although no changes have been observed in the hypertension status and microalbuminuria, HIT partially reverted the high thrombotic microangiopathy incidence in the Dahl salt model, and may explain the reduction in the mortality caused by stroke.

The Clinical Features of Trombotic Microangiopathies Post Transplantation.

B The prevalence, clinical features and incidence of thrombotic microangiopathy (TMA) after renal transplantation are not yet described in literature. M Between 1991 and 2011, 2358 kidney transplants were performed in adult recipients in a single transplant center. All clinical data were prospectively collected and maintained in a dedicated database. We retrospectively identified all patients with features of TMA and evaluated the clinical presentation, prevalence and outcome. R From the total cohort of 2358 patients, 72 (3.0%) were identified with TMA in the post-transplant period (based on the presence schistocytes in a blood smear, suppressed haptoglobin levels, with or without thrombi in a renal biopsy). The clinical presentation was variable: 65 patients (90%) developed anemia, 54 (75%) had thrombocytopenia. Increased bilirubin levels were seen in 23 (32%) patients and an elevated LDH in 69 (95%) of patients. Of the 72 patients diagnosed with TMA after transplantation, 7 were caused by a recurrence of atypical hemolytic uremic syndrome, 1 case was explained by a flare of sickle cell anemia, 1 case was likely associated with sirolimus toxicity, 2 cases were associated with severe opportunistic infections (1 PCP, 1 invasive Aspergillus infection). In 41 patients, there were reported concomitant bacterial infections. In 65 patients, renal allograft biopsies were available at time of TMA. Acute T cell mediated rejection was diagnosed in 44 patients (67.7%), acute antibody-mediated rejection in 7 (11%) of patients with TMA. 51 (70.8%) patients were treated with a calcineurin inhibitor. In 18 patients (25%), TMA was associated with a single potential etiology; in 30 patients (42%) multiple underlying conditions could have explained the occurrence of TMA. In 24 cases (33.3%) there was no clear cause detectable apart from the use of a CNI in 20 cases (27.7%). Of the 72 patients with TMA, 8 (11.1%) patients underwent plasmapheresis and 29 (40%) needed dialysis treatment. Graft loss occurred in 44 (61.1%) patients, with a mean post-tx graft survival of 3.2 ± 1.2 years. C Thrombotic microangiopathy after kidney transplantation is a rare but clinically relevant condition with a very diverse clinical presentation. The etiology is often multifactorial, but in a substantial number of cases no clear cause can be identified. The majority of patients with TMA loose graft function within the first few years after transplantation.

Thrombotic microangiopathy in renal allografts

Thrombotic microangiopathy (TMA) is a serious complication of renal transplantation. It is a morphological expression of various etiological factors. In a renal allograft, TMA can occur de novo or be a recurrent disease. The aim of this study was to analyze the etiological factors and observe the changing trends of TMA with respect to emerging new etiological factors. We evaluated 131 graft biopsies over a period of 2½ years (2010-2012). All the renal biopsies were formalin fixed, paraffin embedded. Twenty serial sections were studied. Stains routinely used were Hematoxylin and Eosin, Periodic Acid Schiff, Massons Trichrome and Silver Methenamine stains. C4d by immunohistochemical method was done on all graft biopsies. Incidence of TMA in our series was 9.1%. Out of the 12 cases, five were associated with calcineurin inhibitor toxicity, three were diagnosed as acute antibody-mediated rejection, and two were recurrent haemolytic uremic syndrome. One patient developed haemolytic uremic syndrome on treatment with sirolimus and one patient was cytomegalovirus positive on treatment with ganciclovir, developed haemolytic uremic syndrome during treatment course. This study describes a spectrum of etiological factors for thrombotic mciroangiopathy ranging from common cause like calcineurin inhibitor toxicity to rare cause like ganciclovir induced TMA.

Prophylaxis with Sirolimus and Tacrolimus ± Antithymocyte Globulin Reduces the Risk of Acute Graft-versus-Host Disease without an Overall Survival Benefit Following Allogeneic Stem Cell Transplantation

Methotrexate (MTX) is a standard agent used in combination with calcineurin inhibitors for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic cell (HCT) transplantation. We retrospectively compared the incidence of acute GVHD (aGVHD), transplant-related morbidity, and mortality in patients given sirolimus/tacrolimus ± antithymocyte globulin (ATG) versus MTX/tacrolimus or cyclosporine and allogeneic transplantation for hematologic malignancies. Between January 1, 2005, and April 30, 2009, 106 consecutive patients received peripheral blood HCT or bone marrow grafts after 1 of 6 myeloablative conditioning regimens. The incidence of grade II-IV aGVHD was 18.6% in patients who received sirolimus/tacrolimus compared to 48.9% who received MTX (P = .001). The incidence of grade III-IV aGVHD was 5% and 17% (P = .045), respectively. There was no difference in overall survival (OS) between the groups (P=.160). Chronic GVHD (cGVHD) occurred in 40.4% who received sirolimus and 41.9% receiving MTX (P = .89). The incidence of thrombotic microangiopathy or interstitial pneumonitis was not significantly different between groups. The reduction in the risk of severe aGVHD was offset by an increased (20% versus 4%, P=.015) incidence of and mortality from sinusoidal obstructive syndrome (SOS). Sirolimus/tacrolimus appears to reduce the incidence of aGVHD after conventional allotransplantion compared to MTX-calcineurin inhibitor prophylaxis; however, this did not improve survival.

A phase II pilot study of tacrolimus/sirolimus GVHD prophylaxis for sibling donor hematopoietic stem cell transplantation using 3 conditioning regimens

AbstractCombination tacrolimus and sirolimus graft-versus-host disease (GVHD) prophylaxis for allogeneic transplant in patients conditioned with a fractionated total body irradiation–based regimen has shown encouraging results. We studied this prophylaxis combination in 85 patients receiving a matched-sibling transplant conditioned with 3 different regimens:fludarabine-melphalan (n = 46); total body irradiation–etoposide (n = 28), and busulfan-cyclophosphamide (n = 11). The conditioning regimens were completed on day −4. Sirolimus and tacrolimus were started on day −3 to avoid overlap with conditioning therapy. All patients engrafted, with a median time to neutrophil engraftment of 15 days. The cumulative incidence of acute GVHD grades II to IV and III to IV was 43% and 19%, respectively, with no significant difference by conditioning regimen. The 2-year cumulative incidence of chronic GVHD was 46%. With a median follow-up of 26 months, disease-free survival was 58% and overall survival, 66%. The day-100 and 2-year nonrelapse mortality was 4.8% and 10.2%, respectively. The overall incidence of thrombotic microangiopathy was 19%, and it was significantly higher with busulfan/cyclophosphamide (55%, P = .005). Tacrolimus plus sirolimus is an effective combination for acute GVHD prophylaxis and is associated with very low nonrelapse mortality. Thrombotic microangiopathy is a significant complication with this regimen, particularly in patients receiving busulfan/cyclophosphamide.

Thrombotic microangiopathy after simultaneous pancreas?kidney transplantation

Thrombotic microangiopathy (TMA) is rare after transplantation and is associated with a high incidence of kidney graft dysfunction. Between December 2000 and March 2006, 136 simultaneous pancreas-kidney transplantations were performed with an incidence of TMA of 5.1% (71.4% localized to kidney allograft). All cases were diagnosed during the first three months and were attributed to tacrolimus; 74% were women. Systemic TMA presented higher values of lactate dehydrogenase (2658 +/- 659 U/L vs. 1331 +/- 473 U/L, p = 0.04) and a greater decrease in hematocrit (45.8 +/- 17.7% vs. 19.2 +/- 6%, p = 0.02) than in localized TMA. Acute kidney rejection complicated almost 90% of the cases with 43% of kidney graft lost. Tacrolimus was switched to sirolimus and fresh-frozen plasma was administered. Creatinine clearance after a mean follow-up of two yr was 100.7 mL/min/1.73 m(2) and 57.9 mL/min/1.73 m(2) in patients with systemic and localized TMA, respectively. In conclusion, sirolimus is an alternative to TMA associated with tacrolimus.

Risk factor analysis for thrombotic microangiopathy after reduced-intensity or myeloablative allogeneic hematopoietic stem cell transplantation

Thrombotic microangiopathy (TMA) impairs long-term survival after allogeneic hematopoietic stem cell transplantation (HSCT). As the allogeneic HSCT procedure has developed, addressing risk factors for TMA has become more complicated. The aim of this study was to investigate the impact of transplant-associated factors on TMA incidence in patients who have undergone HSCT in various settings. One hundred twenty-three consecutive allogeneic HSCT patients with hematologic diseases receiving myeloablative and reduced-intensity conditioning were evaluated retrospectively. Of 123 patients, 22 (17.9%) developed TMA after HSCT. Multivariate analysis showed the significance of GVHD grade II-IV, and the use of FK506 and the use of high-dose busulfan (Bu) (16 mg/kg) persisted. The hazard ratios of the use of FK506, the use of high-dose Bu (16 mg/kg), and GVHD grade II-IV for TMA were 8.7 (95% CI 2.0-37), 5.7 (95% CI 1.5-21), and 3.4 (95% CI 1.3-9.1), respectively. In the present study, reduced-intensity conditioning did not have an advantage over myeloablative conditioning in decreasing the incidence of TMA after HSCT. Our results also showed that high-dose Bu (16 mg/kg) for the conditioning and FK506 for the prophylaxis of GVHD might contribute more significantly to TMA onset after HSCT than other agents.

Thrombotic Microangiopathy™ after Allogeneic Peripheral Blood Stem Cell Transplantation with Nonmyeloablative Conditioning (NMSCT) Compared with Myeloablative Conditioning (MSCT).

Background: Thrombotic microangiopathy (TM) is a severe complication of allogeneic transplantation. The use of CsA for GvHD prophylaxis and unrelated donor appear to be the most significant risk factors for TM after transplantation with conventional myeloablative conditioning (MSCT). Allogeneic transplantation with reduced-intensity conditioning (RIC) is associated with a similar risk of TM, but TM has never been studied after NMSCT.Purpose: To determine the risk factors, incidence and outcome of TM in NMSCT compared to MSCT.Patients: Consecutive patients undergoing NMSCT (group 1, n=103) or MSCT (group 2, n=136) in our center between 1995 and 2004 were retrospectively analysed for TM. Median age was 55 vs 34 yrs in groups 1 and 2 respectively (p<0.0001). Donor was unrelated for 52% of the patients in group 1 and for 38% in group 2 (p=0.0287).Results: TM was diagnosed in 18 (20%) and in 30 (26%) patients in groups 1 and 2, respectively (NS). Most cases were grade 2 TM (18/18 in group 1 and 24/30 in group 1, NS). Neurological signs were present in 50% of the patients in group 1 and 57% in group 2 (NS). In both groups, TM was significantly associated with unrelated donor (p=0.0476 in group 1, p=0.0005 in group 2) and with CMV disease (p=0.0332 in group 1, p=0.0346 in group 2) but not CMV infection. AGvHD of all grades was correlated with TM in group 1 (p=0.0004) but only severe (grade 3–4) AGvHD in group 2 (p<0.0001). Median time of onset of TM was 39 (range 18–157) days in group 1 and 38 (range 0–428) in group 2. First line treatment consisted in switching GvHD prophylaxis to alternative treatment (including tacrolimus) in 54% of the patients and plasmaphereses (36±10 in group 1 and 21±4 in group 2) in 63%. Vincristine (in 11% and 13% of the patients in groups 1 and 2, respectively) and other treatments were rarely used. Forty-four % of the patients died without achieving resolution of their TM in group 1, and 50% in group 2 (NS). For patients who responded to therapy, median duration of TM was 57 (range 5–165) days in group 1 and 46 (range 5–163) days in group 2 (NS). In group 1, the 100-d and 1-yr survival rates were 64% and 28% for patients who developed TM, and 84% and 69% for those without TM, respectively (p=0.0002). In group 2, survival was also significantly reduced in the case of TM (48% vs 70% at day 100 and 23% vs 53% at 1 yr, respectively, p=0.0126).Conclusion: TM remains a frequent and severe complication of allografting. Its incidence and severity in NMSCT is not decreased compared to MSCT and the same factors appear to contribute to its development.

Thrombotic microangiopathy in United States long-term dialysis patients

The incidence, risk factors, recurrence rates and prognosis of thrombotic microangiopathy (TMA) among long-term dialysis patients in the United States have not been previously described in a national population. 272 024 Medicare primary patients in the United States Renal Data System (USRDS) initiated on end-stage renal disease (ESRD) therapy between 1 April 1995 and 31 December 1999 with Medicare as primary payer were analysed in a retrospective cohort study of USRDS of TMA. Cox regression was used to calculate adjusted hazard ratios (AHR) for risk of TMA and risk of death after TMA. The incidence of TMA in the first year of dialysis was 0.5% overall. Among patients with renal failure due to haemolytic uraemic syndrome (HUS), the incidence of TMA was highest in the first year of dialysis (HUS, 11.3% first year, 4.5% per year thereafter), while among patients without HUS the incidence of TMA was much lower and more constant over time (0.3% per year). In Cox regression analysis, independent risk factors for TMA were renal failure due to HUS (adjusted hazard ratio (AHR) 179, 95% CI 95-338), paediatric age (<or=18 years vs older, AHR 2.59, 95% CI 1.48-4.55), female gender (AHR 1.99, 95% CI 1.43-2.78), and systemic lupus erythematosus (SLE, AHR 3.66, 95% CI 1.49-8.51). One-year survival after TMA was poor at 58% (AHR for mortality 2.04, 95% CI 1.23-3.38). TMA is an uncommon cause of hospitalization after dialysis, but does recur in patients with HUS at a substantial rate. Younger age and SLE were risk factors for new onset TMA, which was associated with poor survival. Vigilant monitoring of select patients with HUS-related ESRD and higher-risk patients with SLE is warranted in the dialysis population.

Thrombotic Microangiopathy after Allogeneic Blood and Marrow Transplantation Is Associated with Dose-Intensive Myeloablative Conditioning Regimens, Unrelated Donor, and Methylprednisolone T-Cell Depletion

Allogeneic blood and marrow transplantation (BMT)-associated thrombotic microangiopathy (TM) contributes to transplant-related morbidity and mortality. This report examines the incidence of and risk factors for allogeneic BMT-associated TM in two patient cohorts treated before and after changes in myeloablative conditioning regimen intensity (high vs. standard intensity). Cohort 1 includes 153 consecutive allogeneic BMT patients who underwent transplantation between April 1994 and October 1997 with an allogeneic BMT-associated TM crude incidence of 12%. Cohort 2 includes 75 consecutive allogeneic BMT patients who underwent transplantation from November 1997 to November 2000 with an allogeneic BMT-associated TM crude incidence of 1%. In cohort 1, matched unrelated donor transplant and methylprednisolone (MP) T-cell depletion (TCD) of donor bone marrow were significantly associated with allogeneic BMT-associated TM by univariate analysis; therefore, a logistic model incorporating these effects was constructed to calculate the expected number of allogeneic BMT-associated TM cases in cohort 2. Seven cases would have been expected, but only one was observed (P = 0.003; bayesian predictive test). The multivariate analysis of both cohorts yielded MP-TCD (P<0.001), high-intensity myeloablative conditioning regimens used in cohort 1 (P = 0.02), and matched unrelated donor (P = 0.03) as significant predictors of time to allogeneic BMT-associated TM. Avoidance of high-intensity conditioning regimens may decrease the incidence of allogeneic BMT-associated TM.

Sirolimus and Thrombotic Microangiopathy after Allogeneic Stem Cell Transplantation.

Sirolimus (SRL) is a novel immunosuppressive agent that has been demonstrated to reduce GVHD and minimize morbidity after allogeneic stem cell transplantation (alloSCT). We have described a syndrome of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolysis, thrombocytopenia, and renal dysfunction, whose incidence is increased when SRL is used in association with calcineurin inhibitors (CIs) but not with SRL monotherapy. To determine if SRL use potentiates the effects of CIs on TMA incidence and risk factors, we performed a retrospective cohort analysis of subjects who underwent alloSCT between 1997 and 2003.Methods: Subjects who received a SRL-containing GVHD prophylaxis after a myeloablative preparative regimen were compared with a cohort who received a non-SRL regimen. All subjects received CIs. Diagnosis of TMA required the simultaneous occurrence of: (1) creatinine elevation >2 mg/dL or >50% above baseline, (2) schistocytosis, (3) elevated LDH, and (4) no laboratory evidence of disseminated intravascular coagulopathy.Results: 111 patients who received SRL were compared with 216 patients who received no SRL during the first 100 days after alloSCT. The two groups of patients were balanced for demographic parameters; however, more patients in the SRL group received peripheral blood stem cells (50.5 vs. 18.1%, p<0.01) and had unrelated donors (58.6 vs. 42.6%, p<0.01). The incidence of TMA in the SRL group was 10.8% in comparison with an incidence of 4.2% in the non-SRL group (OR 2.57, p=0.03). Patients who received SRL developed TMA earlier than those who did not receive SRL (median 25 vs. 58 days, p=0.04). At the time of TMA diagnosis, median blood levels of immunosuppressive medications were in their respective therapeutic ranges: SRL (study group) 6.1 ng/ml, tacrolimus (study group) 9.9 ng/ml, tacrolimus (control group) 9.1 ng/ml; cyclosporine (control group) 418 ng/ml. In a multivariable logistic regression model, only the use of SRL (Adjusted Exact OR 3.49, p =0.02) and grade II-IV acute GVHD (Adjusted Exact OR 6.60, p = 0.0002) predicted the occurrence of TMA. Treatment of TMA consisted of discontinuation or dose adjustment of CIs. SRL was discontinued or dosed according to serum level. Two subjects in each group required temporary hemodialysis, and 3 subjects (1 SRL, 2 non-SRL) underwent plasmapheresis. 78% of surviving SRL-treated subjects regained normal renal function. No subject had a TMA recurrence if SRL was reintroduced. Overall survival after TMA diagnosis was better for SRL patients than non-SRL patients (58.3 vs. 11.1%, log rank p=0.02).Conclusion: SRL use is associated with an increased risk of TMA after alloSCT and may act by potentiating the effects of CIs. TMA associated with SRL appears reversible and does not affect overall survival after alloSCT. A careful monitoring strategy for TMA should be employed as part of a SRL-containing GVHD prophylaxis regimen.

Increased Risk of Thrombotic Microangiopathy in Patients Receiving a Cyclosporin–Sirolimus Combination

A single-center cohort study of kidney and kidney–pancreas recipients was conducted to evaluate the association between new immunosuppressive regimens and risk of thrombotic microangiopathy (TMA). From January 1st,1996 to December 31, 2002, 368 patients received a kidney or kidney–pancreas transplant at our center. Four immunosuppressive regimens were evaluated as potential risk factors of TMA: cyclosporin + mycophenolate mofetil (CsA + MMF), cyclosporin + sirolimus (CsA + SRL), tacrolimus + myophenolate mofetil (FK + MMF), and tacrolimus + sirolimus (FK + SRL). Thirteen patients developed biopsy-proven TMA in the absence of vascular rejection. The incidence of TMA was significantly different in the four immunosuppressive regimens studied (p < 0.001). The incidence of TMA was highest in the CsA + SRL group (20.7%). The relative risk of TMA was 16.1 [95% confidence interval (CI): 4.3–60.8] for patients in the CsA + SRL group as compared with those in the FK + MMF group. We also investigated in vitro the pathophysiological basis of this association. The CsA–SRL combination was found to be the only regimen that concomitantly displayed pro-necrotic and anti-angiogenic activities on arterial endothelial cells. We propose that this combination concurs to development of TMA through dual activities on endothelial cell death and repair.