Thrombotic Thrombocytopenic Purpura-hemolytic Uremic Syndrome Research Articles

A pediatric neurologic assessment score may drive the eculizumab-based treatment of Escherichia coli-related hemolytic uremic syndrome with neurological involvement

Thrombotic microangiopathy (TMA) is a clinical syndrome encompassing a large group of rare but severe disorders including thrombotic thrombocytopenic purpura (TTP) and both typical and atypical forms of hemolytic uremic syndrome (HUS). The key role of the complement system is well known in TTP and atypical HUS, but recent reports describe its involvement in the pathogenesis of HUS secondary to gastrointestinal infections due to Shiga toxin-producing Escherichia coli (STEC). TMA mainly affects the kidney, but extra-renal complications are frequently described. The involvement of the central nervous system (CNS) represents often a life-threatening condition and it can result in serious long-term disability in HUS patients who overcome the acute phase of illness. In the present study, we retrospectively analyzed a pediatric cohort of a single tertiary pediatric hospital in Southern Italy, in which this complication occurred in 12/54 children (22% of cases), of whom five with severe neurological involvement had been successfully treated with eculizumab. The great clinical variability of brain injury in our cohort has led us to retrospectively build a "neurological score" useful to assess the clinical severity of neurologic involvement. Subjects with higher neurologic score due to the most severe CNS involvement resulted in the group of patients early treated with eculizumab, obtaining a good clinical response (four out five patients). In conclusion, the early treatment with eculizumab in children with severe neurological involvement during STEC-HUS was associated with complete regression of both acute kidney injury (AKI) and neurological lesions observed at magnetic resonance imaging (MRI). A "neurological score" may be a useful tool to drive the early treatment of CNS complications in STEC-HUS with eculizumab, although future perspective controlled studies are urgently needed to validate this therapeutic approach.

Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome

Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome is an acute illness with abnormalities in multiple organ systems. Patients typically present with thrombotic microangiopathy, thrombocytopenia, and microangiopathic hemolytic anemia without another apparent cause. Additional features include fever, neurologic, and renal abnormalities depending on the site of microangiopathic damage. Potential causes include congenital deficiencies, Shiga-Toxin producing bacteria, numerous drugs, factors related to malignancy, allogeneic hematopoietic cell transplant, cardiovascular surgery, and pregnancy. A medical emergency, appropriate treatment needs to be initiated promptly or the disease can be fatal. Plasma exchange is the initial treatment of choice, but plasma infusion can be used until plasma exchange is available. Adjunctive treatment with glucocorticoids may be used in certain scenarios. If left untreated, the syndrome typically progressively worsens. Affected individuals experience irreversible renal failure, progressive neurological deterioration, cardiac ischemia, and death. With a prompt recognition of the disease and treatment initiation, patients have a better prognosis and mortality rate.

Microangiopathic Hemolytic Anemia and Thrombocytopenia in Patients With Cancer.

The unexpected occurrence of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia and thrombocytopenia, in a patient with cancer requires urgent diagnosis and appropriate management. TMA is a term used to describe multiple syndromes caused by microvascular thrombosis, including thrombotic thrombocytopenic purpura (TTP), Shiga toxin-mediated hemolytic uremic syndrome, and complement-mediated TMA. In patients with cancer, systemic microvascular metastases and bone marrow involvement can cause microangiopathic hemolytic anemia and thrombocytopenia. This occurs most often in patients with known metastatic cancer, but microangiopathic hemolytic anemia and thrombocytopenia may occur unexpectedly in patients without known metastatic disease or be the presenting features of undiagnosed cancer. TMA may also be caused by commonly used chemotherapy agents, either through dose-dependent toxicity or an acute immune-mediated reaction. These causes of TMA must be distinguished from TTP, which results from a severe deficiency of ADAMTS13 and is the most common cause of TMA among adults without cancer. The importance of this distinction is to avoid inappropriate use of plasma exchange, which is associated with major complications. Plasma exchange is the essential treatment for TTP, but it has no known benefit for patients with cancer-induced or drug-induced TMA. We will describe cancer-induced and drug-induced TMA using the experience of the Oklahoma TTP-Hemolytic Uremic Syndrome Registry and data from a systematic review of all published reports of drug-induced TMA. We will illustrate the principles of evaluation and management of these disorders with patients' stories.

Re-examination of 30-day survival and relapse rates in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.

Background and ObjectivesThrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are characterized by microangiopathic hemolytic anemia and thrombocytopenia. Interestingly, markedly different survival rates have been reported despite increases in survivability. We studied TTP-HUS 30-day mortality and relapse rates of patients who received TPE at our institution and compared them to published data.Patients and MethodsRetrospective study analyzed 30-day mortality and relapse rates attributed to TTP-HUS from 01/01/2008 to 12/31/2012 and compared them to comparable literature reporting mortality and survival. Studies describing other etiologies for TPE and different mortality time interval were excluded.ResultsFifty-nine patients were analyzed and all were initially treated with TPE and corticosteroids. Eleven patients were classified as not having TTP-HUS due to testing or clinical reassessment which ruled in other etiologies, and 18/59 patients had ADAMTS13 activity <10%. Of remaining patients, 36/48 (75%) were diagnosed as idiopathic and 12/48 (25%) as secondary TTP-HUS. Patients received a mean of 12 TPEs (range 1-42); 42/48 (87.5%) patients had ADAMTS13 activity measured; complete response obtained in 39/48 (81.2%) patients (platelet count >100 x 109/L); partial response in 4/48 (8%); and 5/48 (10.4%) did not have increases in platelet counts (2/5 of these patients died within the study period). Forty percent of patients obtained platelet counts >150 x 109/L. Overall 30-day mortality for our patient cohort was 6.7% (4/59). Comparison of our mortality rate to combined data of five published studies of 16% (92/571) showed a significant difference, p = 0.04. Our relapse rate was 18.6% (11/59) similar to previous reports.ConclusionsWide differences in mortality may be due to grouping of two distinct pathologic entities under TTP-HUS; and presence of confounding factors in the patient populations under study such as co-morbidities, promptness of TPE initiation, delay in diagnosis and therapeutic practice.

Report of Rare Urachal Carcinoma Presenting with Thrombocytopenia and Microangiopathic Hemolytic Anemia

Introduction:Thrombotic microangiopathy (TMA) is clinical syndrome characterized by microvascular thrombosis, consumptive thrombocytopenia and microangiopathic hemolytic anemia (MAHA). It is a feature of a number of clinical conditions, most prominently thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) and rarely an initial manifestation of systemic malignancy.Case:A previously healthy 31-year-old black woman presented to the emergency department with a 2 week history of lower back pain and hematuria and 1 week history of dyspnea on exertion and dizziness. She denied diarrhea, hematochezia, fever, or abdominal pain. Physical findings were unremarkable with normal blood pressure. Initial laboratory results revealed a white blood cell count of 4.4 x103/µL, hemoglobin of 4.4 g/dL, hematocrit 12.9%, platelets 43 x103/µL, absolute reticulocyte count 259.8 x103/µL, reticulocyte percentage 23.1%, haptoglobin <10 L mg/dL, LDH 1424 units/L, creatinine 0.7 mg/dL, total bilirubin 1.6 mg/dL, negative pregnancy test, and 10-15 white blood cells and >50 red blood cells per high powered field on microscopic urinalysis. Coombs test results were negative, the coagulation profile was normal, and peripheral blood smear revealed evidence of thrombocytopenia and MAHA (figure 1a). Diagnosis of TTP was made and treatment with daily therapeutic plasma exchange (TPE) was initiated. On hospital day 4, ADAMTS13 level drawn at diagnosis before initiation of plasma exchange returned at 94%, prompting further investigation as to the cause of her TMA. Serologic tests for hepatitis B & C virus, human immunodeficiency virus, antinuclear antibody (ANA), cardiolipin and beta-2 glycoprotein antibodies and computerized tomography (CT) scan of the abdomen and pelvis were all negative. Despite daily TPE for 6 days, she remained thrombocytopenic and continued to have ongoing hemolysis. Therefore, on hospital day 6, bone marrow aspiration and biopsy (figure 1b) was performed which showed a normocellular bone marrow for age (cellularity 70%) with full-spectrum trinlineage hematopoiesis, involved by metastatic signet-cell ring carcinoma. Immunostains were positive for CK7, CK20, CK 8/18, CDX2, pancytokeratin, and negative for PAX-8 and mammoglobin. TPE was discontinued and she was supported with packed red blood cell and platelet transfusions.Positron emission tomography–computed tomography (PET-CT) revealed a heterogeneously enhancing mass in the midline superior anterior wall of the bladder measuring 2.7 x 5.1 cm, but without abnormal uptake on PET. She underwent cystourethroscopy and a transurethral resection of bladder tumor which revealed a 6 cm solid sessile mass. Final pathology confirmed the diagnosis of moderate to poorly differentiated invasive urachal adenocarcinoma with mucinous and signet-ring cell features.Given the presence of metastatic disease, she was treated with a chemotherapy regimen consisting of cisplatin, fluorouracil, and leucovorin on days 1 through 5. Gemcitabine was held due to elevated liver transaminases. On day 1 of treatment, platelet count was 24 x103/µL and hemoglobin 8.1 g/dL. By treatment day 7, platelets had risen to 79 x103/µL. She last required a PRBC transfusion on treatment day 4.Discussion:TMA can occur in a variety of disorders, including TTP, HUS, malignant hypertension, scleroderma, antiphospholipid antibody syndrome, systemic lupus erythematosus, preeclampsia, HIV infection, and disseminated malignancy. Patients presenting with evidence of TMA and thrombocytopenia should elicit a high clinical suspicion for TTP and be urgently treated with plasma exchange. Deficiency of the von Willebrand factor-cleaving metalloproteinase ADAMTS13, or the presence of antibodies to ADAMTS13 plays a key role in the pathogenesis of primary TTP, although these findings are not necessary to make the diagnosis. However, patients with a high or normal ADAMTS13 level and without antibodies to ADAMTS13, especially those who do not improve with plasma exchange, should prompt an investigation for other causes of TMA. To our knowledge, we report the first case of metastatic urachal carcinoma presenting with features of MAHA and thrombocytopenia.Conclusion:TMA associated with malignancy is a rare, but potentially fatal condition. Recognition of this rare entity is critical to the initiation of appropriate treatment of underlying malignancy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

P046 - Cumulative review of thrombotic microangiopathy, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome reports with SC interferon beta-1a

Background/objectives Rare cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura or hemolytic uremic syndrome have been reported with interferon beta products. This was a cumulative review of thrombotic microangiopathy cases recorded in a Global Safety Database for subcutaneous interferon beta-1a. Methods Search criteria were all reported cases, serious and non-serious, from all sources (including non-healthcare professionals and clinical trial reports), regardless of event ranking and causality assessment by reporter or Company; data lock was 03 May 2014. Results Ninety one cases with 105 events were retrieved; 76.9% (70/91) patients were female, consistent with the underlying disease of multiple sclerosis. Time-to-onset varied from 2 months to 14 years; 31.9% events occurred within 2-years of treatment initiation. 7 patients had a fatal outcome (5 were secondary to other causes; 2 had insufficient information). 44 patients recovered, 32 had not recovered at the time of the report and in 8 cases the outcome was not reported/unknown. Treatment was discontinued in 84.6% (77/91). In 67.0% (61/91), a causal association between treatment and the occurrence of thrombotic microangiopathy, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome was suspected. Risk factors and/or confounding factors were present in 41/91 cases (45.1%). Early prodromal syndrome or specific patterns were not detected although 55.0% (50/91) contained insufficient information. The overall reporting rate of thrombotic microangiopathy, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome was 7.2 per 100,000 patient-years. Reporting rates for human serum albumin-containing versus human serum albumin-free formulations were 5.72 and 7.68 per 100,000 patient-years, respectively. Conclusions No new signal relating specifically to increased frequency of thrombotic microangiopathy, as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome with the human serum albumin-free formulation was detected and no additional risk mitigation measures were required regarding the different formulations. The benefit-risk balance of subcutaneous interferon beta-1a remains positive and routine pharmacovigilance monitoring is appropriate.

Feasibility of Pediatric Plasma Apheresis in Intensive Care Settings

Therapeutic plasma apheresis or exchange (TPE) in the pediatric population is technically challenging. Moreover, there is generally an apprehension in using TPE in children compared to adults. Recently, usage of TPE has evolved and is now being used in heterogenous clinical conditions. Its usefulness is classified by the American Society for Apheresis (ASFA) into various categories ranging from I to IV. The objective of this paper was to review the procedure in context of clinical indications, complications and outcomes in children. For this purpose, we retrospectively reviewed all TPE procedures performed on inpatients of 3 to 16 years of age during a 6-year period (2007-2012). A total of 130 procedures were performed on 28 patients (M : F ratio of 1:1) with median age (range) of 8.8 (4-16) years. All procedures were done using the continuous cell-separator centrifugal method. Due to organ dysfunctions, the majority of procedures (N = 26 of 28 or 92% patients) were performed in the pediatric intensive care unit. Twenty-three, four and one patient belonged to ASFA categories I, II and III, respectively. The most common indications were neurological disorders (N = 13 or 46.4%), comprised of Guillain-Barré syndrome (N = 10) and myasthenia gravis (N = 3). Hematological disorders (N = 10 or 35.7%) including thrombotic thrombocytopenic purpura-hemolytic uremic syndrome were a close second. Complete recovery was seen in 23 patients (84%). Trivial adverse effects were observed in 18/130 (13.8%) procedures. Major complications including cardiac arrest, hypotension and transfusion-related acute lung injury were observed in 5/130 or 3.8% of procedures. However, there was no procedure-related death though five patients died during treatment due to underlying pathology. In conclusion, TPE is a safe and effective option in sick children for appropriate indications. An experienced staff with sound procedural skills is imperative for successful therapy.

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in relapsing-remitting multiple sclerosis patients on high-dose interferon β

Three women aged 34–47 years old, on high dose interferon beta-1a for relapsing–remitting multiple sclerosis, were hospitalized between 2009–2012 for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Patients sought medical attention for neurological symptoms including cephalalgia, blurred vision, confusion, focal deficits and seizures. All patients presented thrombocytopenia, hemolytic anemia and arterial hypertension. Despite plasma exchanges, corticosteroids and anti-CD20 treatments, all patients progressed towards severe renal insufficiency and one patient died of hemorrhagic shock. In this report we identify a rare but morbid complication of interferon beta-1a treatment associated with female gender, Caucasian background and low body mass index.

Cardiac tuberculoma presenting as thrombotic thrombocytopenic purpura-hemolytic uremic syndrome

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a unique multisystem syndrome. It can present with either chronic or subacute infections. Tuberculosis (TB) is a chronic infection that has been reported to present with TTP-HUS as tuberculous endocarditis in the presence of immunodeficiency and implanted medical devices in regions where TB is endemic. Tuberculomas are space occupying lesions most commonly found in the brain in immunocompromised individuals. Herein, we present a rare association of tuberculosis with endocarditis manifesting as a tuberculoma and presenting as TTP-HUS in an immunocompetent patient and resident of the United States.

Children and adults with thrombotic thrombocytopenic purpura associated with severe, acquired Adamts13 deficiency: Comparison of incidence, demographic and clinical features

Thrombotic thrombocytopenic purpura (TTP) associated with severe, acquired ADAMTS13 deficiency is uncommonly reported in children. The incidence, demographic, and clinical features of these children, compared to adults, have not been described. This study focused on children (<18 years old) and adults with TTP associated with severe, acquired ADAMTS13 deficiency, defined as activity <10%. The incidence rates for TTP in children and adults were calculated from patients enrolled in the Oklahoma TTP-HUS (Hemolytic-Uremic syndrome) Registry, 1996-2012. To describe demographic and clinical features, children with TTP were also identified from a systematic review of published reports and from samples sent to a reference laboratory for analysis of ADAMTS13. The standardized annual incidence rate of TTP in children was 0.09 × 10(6) children per year, 3% of the incidence rate among adults (2.88 × 10(6) adults per year). Among the 79 children who were identified (one from the Oklahoma Registry, 55 from published reports, 23 from the reference laboratory), TTP appeared to be more common among females, similar to the relative increased frequency of women among adults with TTP, and more common in older children. Clinical data were available on 52 children; the frequency of severe renal failure, relapse, treatment with rituximab, and systemic lupus erythematosus in these children was similar to adults with TTP. TTP associated with severe, acquired ADAMTS13 deficiency is uncommon in children. The demographic and clinical features of these children are similar to the features of adults with TTP.

The Oklahoma thrombotic thrombocytopenic purpura-haemolytic uraemic syndrome Registry

SummaryThe Oklahoma Thrombotic Thrombocytopenic Purpura-Haemolytic Uraemic Syndrome (TTPHUS) Registry has a 24 year record of success for collaborative clinical research, education, and patient care. This article tells the story of how the Registry began and it describes the Registry’s structure and function. The Registry provides a model for using a cohort of consecutive patients to investigate a rare disorder. Collaboration between Oklahoma, United States and Bern, Switzerland has been the basis for successful interpretation of Registry data.Registry data have provided new insights into the evaluation and management of TTP. Because recovery from acute episodes of TTP has been assumed to be complete, the increased prevalence of hypertension, diabetes, depression, and death documented by long-term follow-up was unexpected. Registry data have provided opportunities for projects for students and trainees, education of physicians and nurses, and also for patients themselves. During our follow-up, patients have also educated Registry investigators about problems that persist after recovery from an acute episode of TTP. Most important, Registry data have resulted in important improvements for patient care.

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.

Sunitinib-Induced Microangiopathic Hemolytic Anemia with Fatal Outcome

Sunitinib, a new vascular endothelial growth factor receptor inhibitor, has demonstrated activity in renal cell carcinoma and is now widely used in the palliative treatment of patients with metastatic renal cell carcinoma. It is generally well tolerated but has been associated with a low incidence of grade 3 and 4 toxicities including fatigue, diarrhea, anorexia, mucositis, skin toxicity, immune thrombocytopenic purpura, hypertension, hypothyroidism, cytopenias, and decreased cardiac ejection fraction. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a rare condition that is severe and may be fatal. Several medications have been implicated in causing TTP-HUS including clopidogrel, mitomycin C, cisplatin. In this report, we describe a case of atypical HUS-microangiopathic hemolytic anemia during treatment with sunitinib in a patient with metastatic renal cell carcinoma. To our knowledge, this is the fourth case of microangiopathic hemolytic anemia associated with sunitinib described in the literature and the first case with fatal outcome despite treatment with plasmapheresis, dialysis, and withdrawal of sunitinib.

Decreasing frequency of plasma exchange complications in patients treated for thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome, 1996 to 2011 (CME)

Plasma exchange (PEX) treatment for patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) has risk for major complications. Data for PEX-related complications have been prospectively collected on all patients enrolled in the Oklahoma TTP-HUS Registry, 1996 to 2011. PEX-related complications have been defined as major or minor and as central venous catheter related or plasma related. During 15 years, 1996 to 2011, 72 (24%) of 302 consecutive patients had major PEX-related complications. Analysis of five consecutive 3-year cohorts demonstrated that there has been a significant trend for decreasing frequency of all PEX-related major complications (p = 0.014) and central venous catheter-related major complications (p = 0.021) but not for the less common plasma-related major complications (p = 0.380). ADAMTS13 activity was measured in 288 (95%) of the 302 patients. Analysis of the 66 patients with ADAMTS13 activity of less than 10% demonstrated a significant trend for decreasing frequency of PEX-related major complications (p = 0.036); the trend for the 222 patients with ADAMTS13 activity of at least 10% was not significant (p = 0.118). The decreased frequency of PEX-related major complications among patients with ADAMTS13 activity of less than 10% may be related to a significant trend for decreasing duration of PEX treatment (p = 0.040) and decreasing frequency of requirement for more than one central venous catheter (p = 0.044). The decreased duration of PEX treatment may be related to increased use of adjunctive treatments: corticosteroids (p < 0.001) and rituximab (p < 0.001). The frequency of PEX-related major complications has decreased from 1996 to 2011, possibly related to increased use of corticosteroids and rituximab and the decreased duration of PEX required to achieve remission.

Idiopathic combined, autoantibody-mediated ADAMTS-13/factor H deficiency in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in a 17-year-old woman: a case report

IntroductionThrombotic thrombocytopenic purpura-hemolytic uremic syndrome is a life-threatening condition with various etiopathogeneses. Without therapy approximately 90% of all patients die from the disease.Case presentationWe report the case of a 17-year-old Caucasian woman with widespread hematomas and headache. Due to hemolytic anemia, thrombocytopenia, and schistocytosis, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome was suspected and plasma exchange therapy was initiated immediately. Since her thrombocyte level did not increase during the first week of therapy, plasma treatment had to be intensified to a twice-daily schedule. Further diagnostics showed markedly reduced activities of both ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 - also known as von Willebrand factor-cleaving protease) and factor H. Test results for antibodies against both proteins were positive. While plasma exchange therapy was continued, rituximab was given once weekly for four consecutive weeks. After the last dose, thrombocytes and activities of ADAMTS-13 and factor H increased into the normal range. Our patient improved and was discharged from the hospital.ConclusionsSince no clinical symptoms/laboratory findings indicated a malignant or specific autoimmune-mediated disorder, the diagnosis made was thrombotic thrombocytopenic purpura-hemolytic uremic syndrome due to idiopathic combined, autoantibody-mediated ADAMTS-13/factor H deficiency.

Quinine-Induced Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS): Characteristic Clinical Presentation and High Risk for Chronic Kidney Disease (CKD)

Abstract▪2216▪This icon denotes a clinically relevant abstract Introduction:Quinine is the most common cause of drug-induced TTP-HUS in the Oklahoma Registry, 1989–2010. In 52 of all 415 clinically diagnosed patients the cause of TTP-HUS was attributed to a drug; in 25 of these 52 patients, quinine was the suspected drug; in the other 27 patients, chemotherapy agents were the suspected cause in 17, cyclosporine in 3, and 6 different drugs in the other 7 patients. Our goal was to describe the presenting clinical features and long term outcomes of patients with quinine-induced TTP-HUS. Methods:We developed an algorithm to define the causal relation between a drug and the occurrence of TTP-HUS that included patient history (precise time interval between drug exposure and onset of symptoms, occurrence of systemic symptoms with previous exposure to the drug) and documentation of drug-dependent antibodies. Presenting clinical features of patients with quinine induced TTP-HUS were compared to patients with TTP and severe ADAMTS13 deficiency. ADAMTS13 activity has been measured in 299 of 321 (93%) patients, 1995–2010. 68 of 299 (23%) had severe ADAMTS13 deficiency. Glomerular filtration rate (GFR) was calculated by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation (Ann Int Med 2009;150:604). Results:Using this algorithm, 19 of 25 quinine patients had a definite causal relation of quinine to TTP-HUS; among the other 6 quinine patients the causal relation was probable in 1, possible in 2, and unlikely in 3. Among the 27 patients with other suspected drugs, only 1 (gemcitabine) had a definite and 1 (alendronate) had a probable causal relation. In the other 25 patients the causal relationship between the drug and TTP-HUS was only possible or unlikely. The characteristic presenting symptoms of the 19 patients with a definite quinine cause were the sudden onset of fever and chills, gastrointestinal (GI) symptoms, and oliguria. Nine of the 19 patients had had previous systemic symptoms with previous quinine exposure, including two patients with previous episodes of TTP-HUS for which the quinine cause had not been recognized. Sixteen of the 19 patients had ADAMTS13 activity measurements (median, 63%; range 25–100%); their presenting clinical features were significantly different from the 68 patients who had TTP associated with severe ADAMTS13 deficiency, except the frequency of female gender.Clinical featureQuinine (N = 16)ADAMT S13 <10% (N = 68)PAge (median, range)57 (35–77)40 (9–71)<0.001Race (% white)16 (100%)42 (62%)0.002Gender (% women)15 (94%)55 (81%)0.214Fever/chills9 (56%)7 (10%)<0.001GI symptoms16 (100%)47 (69%)0.009Severe neurologic abnormalities1 (6%)35 (52%)<0.001Oliguria/anuria16 (100%)2 (3%)<0.001Hematocrit (%, median, range)23 (19–36)21 (13–33)0.011Platelet count (/uL, median, range)28 (6–54)10 (2–101)<0.001LDH (U/ml, median, range)2762 (339–5878)1372 (256–3909)0.001Creatinine (mg/dL, median, range)8.8 (3.7–15.2)1.5 (0.7–6.6)<0.001Pentad of presenting features4 (25%)4 (6%)0.040Of the 19 patients with a definite quinine cause of TTP-HUS, 1 died and 3 recovered with end-stage renal disease, requiring permanent dialysis and kidney transplantation in two patients. The remaining 15 patients have been followed for a median of 4.8 years (range, 1.2 – 13.8 years). Four have CKD with severely decreased glomerular filtration rate [GFR] (15–29 ml/min/1.73 m2), 7 have CKD with moderately decreased GFR (30–59 ml/min/1.73 m2), and 4 have normal GFR (≥60 ml/min/1.73 m2). Conclusion:Quinine is a common cause of drug-induced TTP-HUS with characteristic clinical features. It is a severe systemic disorder that can cause death and commonly causes CKD. The quinine cause may not be recognized because quinine exposure, from occasional tablets for leg cramps or from tonic water, may be overlooked. Disclosures:No relevant conflicts of interest to declare.

Postendoscopic retrograde cholangiopancreatography pancreatitis

Endothelial injury is perhaps the inciting factor leading to the microangiopathic process that initiates thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS). TTP-HUS after postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis is extremely rare, but potentially is life threatening. Here, we describe a case of a 23-year-old man with a history of choledocholithiasis, who developed TTP-HUS, 2 days after the onset of post-ERCP pancreatitis. It is important that physicians recognize TTP-HUS as one of the potential causes of acute kidney injury in cases of acute pancreatitis and post-ERCP pancreatitis for adult patients, especially when there is concomitant thrombocytopenia and hemolytic anemia. The early initiation of plasma exchange has a major impact on the survival and preservation of renal function. Exchange transfusion of fresh frozen plasma remains the cornerstone treatment of TTP-HUS.

Therapeutic plasma exchange in patients with thrombotic thrombocytopenic purpura–hemolytic uremic syndrome: the 10‐year experience of a single center

Background: Therapeutic plasma exchange (TPE) has been used for the treatment of patients with thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (TTP–HUS). We report the 10‐year treatment results along with the risk factors analyses.Methods: Retrospective analyses were performed on patients who were treated with TPE for TTP–HUS.Results: Fifty‐two patients were included. Secondary causes were identified in 38 patients (73·1%). The others were classified as idiopathic. After a median five sessions of TPE, 26 patients (50·0%) achieved remission. Remission rate in patients with idiopathic and secondary TTP–HUS was 71·4 and 42·1%, respectively. Overall 30‐day mortality rate was 34·6% and median overall survival was 5·2 months. Patients with hematopoietic stem cell transplantation‐associated TTP–HUS did not respond and had poor overall survival. Males had a lower remission rate than females (P = 0·009).Conclusions: TPE was an effective treatment in patients with idiopathic TTP–HUS. Treatment results were various according to etiology and gender.

Thrombotic microangiopathy as a complication of recurrent pancreatitis

Acute pancreatitis as a cause of thrombotic microangiopathy is very rare. We report a case of 40-year-old woman with idiopathic recurrent pancreatitis, who presented with acute pancreatitis complicated by thrombotic microangiopathy. Although thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) has been reported as causing acute pancreatitis, the induction of TTP/HUS by pancreatitis is rare. As far as we are aware this is the first reported case of TTP/HUS in association with pancreatitis in India. Our patient had a complete recovery of her thrombotic microangiopathy following plasma exchange therapy.

Relapsing or refractory idiopathic thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome: the role of rituximab

Idiopathic thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a rare disease responsive to treatment with plasma exchange (PE) but with a high percentage of relapse or refractory patients. A severe deficiency of ADAMTS-13 (<5% of normal activity), congenital or caused by an autoantibody, may be specific for TTP and it has been proposed that severe ADAMTS-13 deficiency now defines TTP. B cells play a key role in both the development and the perpetuation of autoimmunity, suggesting that B-cell depletion could be a valuable treatment approach for patients with idiopathic TTP-HUS. This review of the literature focuses on the role of rituximab, a chimeric monoclonal antibody directed against CD20 antigen expressed by B lymphocytes, in patients with relapsing or refractory TTP-HUS with or without ADAMTS-13 deficiency, suggesting that rituximab may produce clinical remission in a significant proportion of patients. Rituximab therapy reduces plasma requirement and avoids complications related to salvage-immunosuppressive therapy. In conclusion, rituximab provides an effective, well-tolerated, and safe treatment option for patients with idiopathic TTP-HUS, thus giving an alternative approach to the current treatment based on PE.