Diagnosis Of Thrombotic Microangiopathy Research Articles

The spectrum of renal thrombotic microangiopathy in lupus nephritis

IntroductionAmong various lupus renal vascular changes, thrombotic microangiopathy (TMA) presented with the most severe clinical manifestations and high mortality. The pathogenesis of TMA in systemic lupus erythematosus (SLE) was complicated. The aim of this study was to assess clinical manifestations, laboratory characteristics, pathological features and risk factors for clinical outcomes of lupus nephritis patients co-existing with renal TMA in a large cohort in China.MethodsClinical and renal histopathological data of 148 patients with biopsy-proven lupus nephritis were retrospectively analyzed. Serum complement factor H, A Disintegrin and Metalloprotease with Thrombospondin type I repeats 13 (ADAMTS-13) activity, antiphospholipid antibodies and C4d deposition on renal vessels were further detected and analyzed.ResultsIn the 148 patients with lupus nephritis, 36 patients were diagnosed as co-existing with renal TMA based on pathological diagnosis. Among the 36 TMA patients, their clinical diagnoses of renal TMA were as followings: 2 patients combining with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 2 patients combining with anti-phospholipid syndrome, 2 patients with malignant hypertension, 1 patient with scleroderma and the other 29 patients presenting with isolated renal TMA. Compared with the non-renal TMA group, patients with renal TMA had significantly higher urine protein (7.09 ± 4.64 vs. 4.75 ± 3.13 g/24h, P = 0.007) and serum creatinine (159, 86 to 215 vs. 81, 68 to 112 μmol/l, P <0.001), higher scores of total activity indices (AI) (P <0.001), endocapillary hypercellularity (P <0.001), subendothelial hyaline deposits (P = 0.003), interstitial inflammation (P = 0.005), glomerular leukocyte infiltration (P = 0.006), total chronicity indices (CI) (P = 0.033), tubular atrophy (P = 0.004) and interstitial fibrosis (P = 0.018). Patients with renal TMA presented with poorer renal outcome (P = 0.005) compared with the non-TMA group. Renal TMA (hazard ratio (HR): 2.772, 95% confidence interval: 1.009 to 7.617, P = 0.048) was an independent risk factor for renal outcome in patients with lupus nephritis. The renal outcome was poorer for those with both C4d deposition and decreased serum complement factor H in the TMA group (P = 0.007).ConclusionsThere were various causes of renal TMA in lupus nephritis. Complement over-activation via both classical and alternative pathways might play an important role in the pathogenesis of renal TMA in lupus nephritis.

Complement activation in thrombotic microangiopathies

Complement activation in thrombotic microangiopathies

Belatacept Used as Rescue Maintenance Immunosuppression in ABO-Incompatible Living Donor Kidney Transplant

Introduction: Belatacept (Nulojix) is the first T-cell co-stimulation blocking immunosuppressive agent licensed for use in transplantation. It is an effective alternative to ciclosporin in ABO and HLA-antibody compatible adult kidney transplantation. Here we describe a patient successfully maintained on Belatacept following an ABO and HLAantibody incompatible live donor renal transplant. Case report: The patient is a 30-year old male diagnosed with IgA nephropathy in 2008. He became dialysis dependent in January 2011. In September 2011 he received a 2-1-1 mismatched transplant from his wife. He was ABO group O with an anti-A tire of 1:256 against the group A1 donor. CDC and flow cross matching were negative but HLA A3 and A11 DSA were detected by Luminex with MFI of 4754 and 2567 respectively. There was no known allosensitizing stimulus. Immunosuppression comprised IV Rituximab 500mg 3 weeks prior to transplantation, 7 cycles of immunoabsorption and induction with 30mg Alemtuzumab, followed by Tacrolimus, Mycophenolate Mofetil (MMF) and prednisolone. On the day of transplant anti-A titre was 1:8 and DSA undetectable. Surgery was uncomplicated with primary graft function. On post-operative day 5 serum creatinine (SCr) reached 240mmol/L, but on day 7 rose to 289mmol/L. Biopsy demonstrated severe thrombotic microangiopathy (TMA) with multiple microthrombi in glomerular afferent arterioles and capillaries. C4d was diffusely positive, but without peritubular capillaritis, glomerulitis or evidence of T-cell mediated rejection. Anti-A titre was 1:4 and DSA undetectable. A diagnosis of Tacrolimus-related TMA was made, without systemic features of TMA. Tacrolimus was discontinued, 10 cycles of plasma exchange with FFP replacement administered, and sirolimus added to MMF and prednisolone. SCr fell to 140mmol/L. On day 36, the patient developed a swollen leg ipsilateral to his graft. SCr was stable at 136mmol/L but there was significant proteinuria with a urinary ACR of 198mg/mol. CT demonstrated a lymphocele compressing the external iliac vessels. Surgical drainage and fenestration of the collection into the peritoneal cavity resulted in immediate resolution of both the lymphocele and the swollen leg. Both proteinuria and lymphocele were attributed to Sirolimus, which was discontinued. Since Tacrolimus was contraindicated Belatacept was added, initially as a monthly infusion (10mg/kg). Since commencing Belatacept, proteinuria has resolved (ACR 14.5) and SCr remained stable at 130mmol/L. DSA have returned to pre-transplant levels, and anti-A titre is 1:64. Immunosuppression comprises Belatacept 5mg/kg monthly, MMF 1000mg BD and prednisolone 5mg OD. Conclusion: Belatacept use was necessitated by serious adverse reactions to both Tacrolimus and Sirolimus. This case demonstrates the utility of Belatacept as rescue maintenance immunosuppression in an ABO and HLA antibody incompatible transplant.

De Novo Thrombotic Microangiopathy After Kidney Transplantation: Clinical Features, Treatment, and Long-Term Patient and Graft Survival

IntroductionPosttransplant thrombotic microangiopathy (TMA)/hemolytic uremic syndrome (HUS) can occur as a recurrent or de novo disease. MethodsA retrospective single-center observational study was applied in order to examine the incidence and outcomes of de novo TMA/HUS among transplantations performed between 2000 and 2010. Recurrent HUS or antibody-mediated rejections were excluded. ResultsSeventeen (1.1%) among 1549 kidney transplant recipients fulfilled criteria for de novo TMA. The mean follow-up was 572 days (range, 69–1769). Maintenance immunosuppression was prednisone, tacrolimus (TAC), and mycophenolic acid in 14 (82%) patients. Mean age at onset was 40 ± 15 years, and serum creatinine was 6.1 ± 4.1 mg/dL. TMA occurred at a median of 25 days (range, 1–1755) after transplantation. Nine (53%) patients developed TMA within 1 month of transplantation and only 12% after 1 year. Clinical features were anemia (hemoglobin < 10 g/dL) in 9 (53%) patients, thrombocytopenia in 7 (41%), and increased lactate dehydrogenase in 12 (70%). Decreased haptoglobin was observed in 64% and schistocytes in 35%. Calcineurin inhibitor (CNI) withdrawal or reduction was the first step in the management of 10/15 (66%) patients, and 6 (35%) received fresh frozen plasma (FFP) and/or plasmapheresis. TAC was successfully reintroduced in six patients after a median of 17 days. Eight (47%) patients needed dialytic support after TMA diagnosis and 75% remained on dialysis. At 4 years of follow-up, death-censored graft survival was worse for TMA group (43.0% versus 85.6%, log-rank = 0.001; hazard ratio = 3.74) and there was no difference in patient survival (53.1% versus 82.2%, log-rank = 0.24). ConclusionDe novo TMA after kidney transplantation is a rare but severe condition with poor graft outcomes. This syndrome may not be fully manifested, and clinical suspicion is essential for early diagnosis and treatment, based mainly in CNI withdrawal and FFP infusions and/or plasmapheresis.

Fragmented red blood cells automated measurement is a useful parameter to exclude schistocytes on the blood film

The diagnosis of thrombotic microangiopathies (TMA) or disorders that may mimic their features remains difficult. Mechanical hemolytic anemia with the detection of shistocytes on the blood smear is a cornerstone finding to assess the diagnosis, but microscopic evaluation of shistocytes is still problematic with wide interobserver variations. Some of the latest generation automated blood cell counters (ABCC) propose an original quantitative approach of fragmented red cells (FRC), aiming to be equivalent to the microscopic count. This parameter has been poorly evaluated. To assess the predictive value (PV) of this test, we conducted studies comparing automated and microscopic counts of FRC/schistocytes, based on the analysis of thousands samples in four university hospitals and using the 2 ABCC currently available (Siemens ADVIA series, Sysmex XE-2100). Reference range for FRC was <0.3% for the ADVIA and <0.5% for the XE-2100. The presence of FRC below a threshold determined at 1% (ADVIA and XE-2100) had a negative PV close to 100% to exclude the presence of schistocyte on the blood smear, but in relationship with a poor PV value. Our study validated the utility of the immediately available FRC parameter on ABCC to exclude schistocytes and the diagnosis of TMA.

Diagnosis of Intestinal Graft-versus-Host Disease and Thrombotic Microangiopathy after Allogeneic Stem Cell Transplantation

Severe diarrhea is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Acute graft-versus-host disease (GVHD) has been one of the major causes of diarrhea after HSCT, which is triggered by donor-derived cytotoxic T-lymphocytes. On the other hand, intestinal thrombotic microangiopathy (TMA) sometimes coexists with acute GVHD, and intensified immunosuppression to treat acute GVHD could exacerbate intestinal TMA, presumably through the vascular endothelial cell damage. The differential diagnosis between intestinal TMA and acute GVHD of the gut has mainly relied on the pathological findings, as clinical diagnosis of intestinal TMA has not been established. Therefore, we aimed to assess the feasibility of our clinical diagnosis for the patients with diarrhea after HSCT. We made tentative clinical criteria for intestinal TMA and acute GVHD of the gut, based on the clinical manifestations, laboratory data and colonoscopic findings, and started treatment before pathological diagnosis were made. Subsequently, a pathologist retrospectively assessed the accuracy of clinical diagnosis in a blind manner. In this study, we enrolled 19 patients complicating watery diarrhea after HSCT, and diagnosed as having acute GVHD (n = 10), intestinal TMA (n = 3), or both (n = 6) according to our criteria. We demonstrated that our clinical diagnosis for intestinal TMA and acute GVHD of the gut was overall correct, in terms of the response to the therapy and the pathological diagnosis. The present study may provide a clue on making clinical diagnosis of patients with watery diarrhea after HSCT, which enables us to start a prompt therapy.

Elevated Von Willebrand factor propeptide for the diagnosis of thrombotic microangiopathy and for predicting a poor outcome

Thrombotic microangiopathy (TMA) is associated with vascular endothelial cell injury and is sometimes linked with poor outcome. Von Willebrand factor (VWF) propeptide (VWFpp) is considered to be a marker of vascular endothelial cell injury. The plasma levels of VWF, VWFpp, and thrombomodulin (TM) were evaluated for their use in the diagnosis of TMA in 75 patients with TMA. There were 30 TMA patients with marked decreases in ADAMTS13 (TMA/ADAMTS13) and 45 without the decrease (TMA/other). The plasma levels of TM, VWF, and VWFpp values were significantly high in patients with TMA, especially TMA/other group. The plasma levels of TM and VWFpp were significantly high in non-survivor with TMA. In the TMA/other group, the plasma levels of VWFpp were negatively correlated with ADAMTS13 activity. The plasma levels of TM correlated with the renal function, but the plasma levels of VWFpp did not. A ROC analysis indicated that VWFpp and TM were useful markers for the prediction of a poor outcome. These findings suggest that VWFpp is an useful marker for the diagnosis of TMA and for the prediction of poor outcome.

Chronic Kidney Disease, Thrombotic Microangiopathy, and Hypertension Following T Cell-Depleted Hematopoietic Stem Cell Transplantation

Chronic kidney disease (CKD) is now an accepted long-term complication of allogeneic hematopoietic stem cell transplantation. Calcineurin inhibitors (CNI), which are used for prophylaxis and treatment of graft-versus-host disease (GVHD), have been associated with the development of nephrotoxicity. Hypertension (HTN) and thrombotic microangiopathy (TMA) are 2 comorbidities linked to CKD. T cell depletion (TCD) of stem cell grafts can obviate the need for the use of CNI. We conducted a retrospective analysis of 100 patients who underwent TCD transplantation: 30 in group A were conditioned without total-body radiation (TBI) and 70 in group B received a TBI containing regimen. None of the patients received CNI. The median age was 55.5 and 45 years for groups A and B, respectively. Eleven patients developed TMA, all in group B. The 2-year cumulative incidence of sustained CKD was 29.2% and 48.8% in group A and group B, respectively, with a mean follow-up of at least 21 months. CKD free survival was better in the non-TBI group (P = .046). Multivariable survival analysis revealed that exposure to TBI, older age, and TMA were risk factors for CKD. The incidence of new onset or worsening HTN was 6.7% and 25.7% (P = .03) in group A and B, respectively. The use of TBI (P = .0182) and diagnosis of TMA (P = .0006) predisposed patients to the development of HTN using univariable logistic regression models. Thus, despite the absence of CNI, a proportion of these older patients in both groups developed CKD and HTN.

Specific Colonoscopic Findings of Intestinal Graft-Versus-Host Disease, Intestinal TMA, and CMV Colitis After Allogenic Hematopoietic Stem Cell Transplantaion

Background: After allogenic hematopoietic stem cell transplantation (HSCT), significant complications involving the gastrointestinal tract occur, such as graft-versus -host disease (GVHD), thrombotic microangiopathy (TMA), and cytomegalovirus (CMV) colitis. Although the therapeutic strategies for these disorders are completely different, it is difficult to establish the differential diagnosis based on the clinical grounds alone. Little is known about the specific colonoscopic findings of these three disorders. Aim: To clarify the specific colonoscopic findings of intestinal GVHD, intestinal TMA, and CMV colitis. Patients and Methods: Between April 2001 and March 2008, 31 patients suffering from GI symptoms within the first 100 days after allogenic HSCT underwent 38 colonoscopies. The final diagnoses of these patients were made by a retrospective review of the medical records, and all 38 colonoscopic findings were analyzed. We picked up the relatively specific findings such as “spotty redness”, “sloughing of the mucosa”, “tortoiseshell pattern”, “diffuse redness”, and “punched-out ulcer” which are not usually observed in infectious colitis or inflammatory bowel diseases. To examine the diagnostic values of these colonoscopic findings, the sensitivity and, if possible, specificity of these findings for diagnosis were examined, retrospectively. Results: All 38 cases were finally diagnosed as intestinal GVHD. Eight cases were diagnosed as intestinal GVHD overlapping intestinal TMA. One case was diagnosed as intestinal GVHD overlapping CMV colitis. Spotty redness, sloughing of the mucosa, tortoiseshell pattern, diffuse redness, and punched-out ulcer were observed in 19/38 (50.0%), 29/38 (76.3%), 38/38 (100%), 7/38 (18.4%), and 1/38 (2.6%) respectively. Spotty redness, sloughing of the mucosa, and tortoiseshell pattern tended to be frequently observed in intestinal GVHD. Diffuse redness tended to be frequently observed in the cases which were diagnosed as GVHD overlapping intestinal TMA. The calculated sensitivity and specificity of this finding for the diagnosis of intestinal TMA were 75.0% and 96.8%, respectively. In only one case diagnosed as CMV colitis overlapping intestinal GVHD, multiple punched-out ulcers were detected in the descending and sigmoid colon. Conclusions: Specific colonoscopic findings may be valuable for making a differential diagnosis of intestinal GVHD, intestinal TMA, and CMV colitis after HSCT. The proposed specific findings are as follows. 1) Spotty redness, sloughing of the mucosa, and tortoiseshell pattern for intestinal GVHD. 2) Diffuse redness for intestinal TMA. 3) Punched-out ulcer for CMV colitis.

506: ADAMTS 13 Activity in Patients with Suspected Thrombotic Microangiopathy (TMA) after Lung Transplantation

Thrombocytopenia is a frequent complication after lung transplantation and TMA is frequently the cause of this thrombocytopenia. Nevertheless, the diagnosis of TMA is difficult to prove in these patients. It has been shown recently that severe acquired deficiency of ADAMTS 13 activity may be associated with TMA after lung transplantation. [H.Mal, Transplantation 2006; 81:1628-1632]. The aim of this study was to assess the diagnostic value of ADAMTS 13 activity in cases of suspected TMA after lung transplantation.

Renal Thrombotic Microangiopathy after Hematopoietic Cell Transplant

Thrombotic microangiopathy (TMA) is a known complication of hematopoietic cell transplantation (HCT). The etiology and diagnosis of TMA in this patient population is often difficult because thrombocytopenia, microangiopathic hemolytic anemia, and kidney injury occur frequently in HCT recipients, and are the result of a variety of insults. The authors reviewed renal pathology and clinical data from HCT patients to determine the prevalence of TMA and to identify correlative factors for developing TMA in the kidney. Kidney tissue was evaluated from 314 consecutive autopsies on patients who died after their first HCT (received between 1992 and 1999). Renal pathology was classified into three groups: (1) no renal thrombus (65%), (2) TMA (20%), and (3) isolated thrombosis (15%). Logistic regression models estimated the associations between each histologic category and clinical parameters: donor and recipient gender, patient age, human leukocyte antigen (HLA) matching of the donor and recipient, total body irradiation (TBI), acute graft versus host disease (GVHD), acute kidney injury, medications, and viral infections. In a multivariate analysis, TMA correlated with acute GVHD grades II to IV, followed by female recipient/male donor, TBI > 1200 cGy, and adenovirus infection. Grades II to IV acute GVHD and female gender were associated with isolated renal thrombus. TMA in HCT recipients is associated with acute GVHD grades II to IV, recipient/donor mismatch, TBI > 1200 cGy, and adenovirus infection.

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

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

Thrombotic Microangiopathy 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 and Other Glomerular Disorders in the HIV-Infected Patient

Various forms of kidney disease have been related directly to human immunodeficiency virus (HIV) viral infection, including HIV-associated nephropathy (HIVAN), immune complex diseases, and thrombotic microangiopathy (TMA). HIVAN and HIV immune complex glomerulonephritides are the most common HIV-specific nephropathies. HIV-associated TMA, although far less common, remains an important consideration. The diagnosis of TMA in HIV, which has a poorly understood pathogenesis, can be suggested by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure, but only definitively diagnosed by kidney biopsy. Not surprisingly, the incidence and prevalence of the HIV-specific entities have declined with the advent of highly active antiretroviral therapy. With this decline, however, other glomerular diseases are of increasing importance in this high-risk population. The differential diagnosis of glomerular disease in an HIV-positive patient is therefore broad. Glomerular diseases seen in this population include classic focal segmental glomerulosclerosis, IgA nephropathy, postinfectious glomerulonephritis, hepatitis B- and C-related glomerulonephritides, and membranous nephropathy. In addition, as the HIV-infected population ages, diabetic and hypertensive nephropathies are likely to become more prevalent. With overlapping presentations of these entities, definitive diagnosis often is difficult, necessitating kidney biopsy. As a consequence of establishing an accurate diagnosis, improved patient outcome can best be accomplished through disease-specific intervention.

Thrombotic Microangiopathy After ABO-Incompatible Living Donor Liver Transplantation: A Case Report

Thrombotic microangiopathy (TMA) has rarely been reported in the setting of liver transplantation. Herein we have reported a successful case of TMA after ABO-incompatible living donor liver transplantation (LDLT) treated with plasma exchange and high-dose intravenous gamma-globulin infusion. A 50-year-old woman was diagnosed with hepatitis C virus-related cirrhosis. We performed an ABO-incompatible LDLT (group B to O) with preoperative plasma exchange to reduce the anti-B hemagglutinin titers to 1:8. The immunosuppressants consisted of tacrolimus, mycophenolate mofetil, and steroid. On postoperative day (POD) 8, her anti-B hemagglutinin titer suddenly increased to 1:64. The serum lactate dehydrogenase (LDH) level was grossly elevated (1518 IU/L). On POD 13, we suspected infection of an intra-abdominal hematoma ( Serratia marcescens) which was drained surgically. On day 5 after the reoperation, thrombocytopenia developed with a platelet count of 3×10 4/mm 3. A peripheral blood film showed severe red blood cell (RBC) fragmentation. Thus, we made a clinical diagnosis of TMA and reduced the tacrolimus dose. We started intensive daily plasma exchange (4 L/d) with fresh frozen plasma and high-dose intravenous gamma-globulin infusions. One week thereafter, thrombocytopenia improved with reduced transfusion requirements. The peripheral blood film showed normal RBC morphology. The serum LDH returned to baseline levels. Four factors were considered to have caused TMA in this case: the prescription of tacrolimus, ABO-incompatible liver transplantation, bacterial infection, and surgical stress. These factors may have all contributed by causing significant endothelial injury and TMA.

The Effectiveness of Measuring for Fragmented Red Cells Using an Automated Hematology Analyzer in Patients With Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA) or thrombotic thrombocytopenic purpura (TTP) is a life-threatening syndrome characterized by increased number of fragmented red cells (FRCs) and thrombocytopenia. FRCs can be measured using the recently developed automated hematology analyzer XE-2100. The normal range for FRCs is 0% to 0.205%, as determined by the automated hematology analyzer XE-2100. The FRC count is significantly elevated in patients with TMA associated with liver transplantation, bone marrow transplantation, or TTP. In patients with TMA after liver transplantation, the FRC count is significantly higher than in those without TMA. In receiver operating characteristic analysis for the diagnosis of TMA, the area under the curve is 0.986, suggesting that FRC is a useful marker for the diagnosis of TMA. When the cutoff value of FRC for TMA is 1.2%, the sensitivity is 90% and the specificity is 96%, indicating that FRC is the most useful screening test for the diagnosis of TMA.

Are Prothrombotic Variants of Platelet Glycoprotein Receptor Polymorphisms Involved in the Pathogenesis of Thrombotic Microangiopathies?

Thrombotic microangiopathies are life-threatening disorders characterized by vascular microthromboses, schistocytic hemolytic anemia, and thrombocytopenia. Although recent research has partially explained the pathogenesis of these rare entities, the determinants contributing to the onset and modulating the severity of thrombotic microangiopathies are largely unknown. The present study assessed the putative role of prothrombotic platelet receptor polymorphisms in thrombotic microangiopathies that have been found to be associated with premature onset of myocardial infarction in predisposed individuals. Thirty-four consecutive patients admitted with the diagnosis of thrombotic microangiopathy and 759 healthy subjects were enrolled. Genotyping of the human platelet antigen (HPA) 2 an the Kozak sequence polymorphism of GP Ibalpha of the platelets' von Willebrand factor receptor glycoprotein (GP) Ib-V-IX, the HPA-1 and the HPA-3 polymorphism of the fibrinogen receptor GP IIb-IIIa (integrin alpha(IIb)beta( 3)) and the HPA-5 and GP Ia 807 C/T polymorphism of the collagen receptor GP Ia-IIa (integrin alpha(2)beta(1)) were determined according to standard procedures. As a result, no significant differences in the prevalence of prothrombotic variants of platelet-receptor polymorphisms between patients and healthy control subjects were observed. However, although not significant, the prothrombotic bb genotype of the HPA-1 polymorphism was more prevalent in the patients. The findings do not provide evidence that platelet receptor polymorphisms are determinants for the onset of thrombotic microangiopathies or predispose to a more severe course. Along with this observation, screening for respective platelet-receptor polymorphisms does not appear to contribute to risk stratification of affected patients.

Diagnosis of de novo localized thrombotic microangiopathy by surveillance biopsy

Thrombotic microangiopathy has been reported in association with calcineurin inhibitors and less frequently with sirolimus in renal transplant patients. The diagnosis of thrombotic microangiopathy is typically made by diagnostic biopsy in the setting of allograft dysfunction. The finding of thrombotic microangiopathy on surveillance biopsy without a significant elevation of baseline serum creatinine is unusual. The optimal treatment of this disorder remains controversial. Treatment strategies have included dose adjustment, drug substitution, plasmapheresis, and intravenous immunoglobulin G. We report a case of de novo thrombotic microangiopathy diagnosed by surveillance biopsy in a patient without hematologic abnormalities or elevated serum creatinine. This patient had resolution of the renal lesion following conversion from tacrolimus to sirolimus-based immunosuppression.

Prognosis and pathological characteristics of five children with non-Shiga toxin-mediated hemolytic uremic syndrome

The three major signs of hemolytic uremic syndrome (HUS) are hemolytic anemia, thrombopenia and acute renal failure. HUS is classified into Shiga toxin-mediated HUS (Stx-HUS) and non-Shiga toxin-mediated HUS (nStx-HUS). The prognosis of nStx-HUS is reported to be less favorable than that of Stx-HUS. Although the association between the prognosis and pathological characteristics of HUS have been reported such that the prognosis was considered to be poor for thrombotic microangiopathy (TMA) with predominant arterial involvement (arterial TMA), good for TMA with predominant glomerular involvement (glomerular TMA) and dependent on the extent of necrosis in cases of renal cortical necrosis, it is not yet clear whether pathological findings are also related to the renal prognosis of nStx-HUS cases. Therefore the purpose of the present paper was to analyze renal biopsy findings and prognosis for five children with nStx-HUS. Clinical records of five cases of nStx-HUS among 74 cases of diagnosed HUS were reviewed, and information and data were summarized. Histological examination of the kidney led to the diagnosis of arterial TMA in three cases, and glomerular TMA and severe renal cortical necrosis in one case each. Analysis of the relationship between renal histological findings and the prognosis found that three patients with arterial TMA and one patient with severe renal cortical necrosis later developed end-stage renal failure while one patient with glomerular TMA has continued to show normal renal function. These findings indicate that pathological findings are closely related to the prognosis in cases of nStx-HUS.

Thrombotic Microangiopathy in a Child With Acute Pancreatitis

Thrombotic Microangiopathy in a Child With Acute Pancreatitis