Daily Plasma Exchange Research Articles

Purpura thrombotique thrombocytopénique et autres syndromes de microangiopathie thrombotique au cours de l’infection par le virus de l’immunodéficience humaine

Human immunodeficiency virus (HIV) infection represents a risk factor for thrombotic microangiopathy. HIV-associated thrombotic microangiopathies encompass two entities with distinct pathophysiology, clinical presentation, treatment and prognosis. Thrombotic thrombocytopenic purpura associated with human immunodeficiency virus is typically characterized by a sudden onset in a patient with a moderate immune deficiency and a few events of opportunistic diseases, and a profound acquired deficiency in the von Willebrand factor cleaving protease ADAMTS13. This diagnosis requires a well-codified management including daily therapeutic plasma exchanges, a highly active antiretroviral therapy and eventually immunomodulatory drugs. The prognosis is good with a response rate and an overall survival comparable to that of HIV-negative thrombotic thrombocytopenic purpura. On the opposite, HIV-associated thrombotic microangiopathy with a progressive onset that occurs in profoundly immunocompromised patients with past history of multiple opportunistic diseases usually have a detectable ADAMTS13 activity and a worse prognosis. Usual treatment is poorly efficient. Forthcoming studies should assess the role of immunomodulatory drugs such as rituximab in the setting of HIV-associated thrombotic microangiopathy, and identify possible risk factors associated with the occurrence of these diseases.

Syndrome hémolytique et urémique avec atteinte neurologique sévère : quelle prise en charge ?

The management of diarrhea-associated hemolytic and uremic syndrome (D(+) HUS) with severe acute neurological involvement continues to be debated. We report on 2 cases and discuss the treatment. CASE REPORT 1: A 2.5-year-old girl presented with generalized seizures during gastroenteritis. Blood tests revealed features of HUS and a pyramidal syndrome was found on physical examination. Brain MRI, 24h after admission, showed lesions in the periventricular and subcortical area. She was started on peritoneal dialysis (PD) and daily plasma exchanges (PE) for 10 days. Her neurological condition improved quickly as well as the findings of the second brain MRI performed after PE. One year later she had no apparent neurological or renal sequelae. CASE REPORT 2: A 2.5-year-old boy presented with generalized seizures during gastroenteritis for 3 days, leading to a diagnosis of HUS. He also had a severe pyramidal syndrome with spastic tetraparesis and aphasia. Brain MRI, 48 h after admission, revealed severe bilateral and symmetric lesions involving the thalami, internal and external capsules, lenticular nuclei, and brainstem. He was started on PD and daily PE for 10 days. Brain MRI performed after PE was unchanged. Clinically, his neurological condition improved slowly with regression of spastic tetraparesis and progressive recovery of motor skills. Nine months later, his renal function is normal but he is still having intensive physiotherapy. Both children have received similar management including 10 PEs started within 48 h after the diagnosis of D(+) HUS with severe neurological involvement, but their neurological outcome appeared to be significantly different. There is no clear proof in the literature concerning the effects of PE in such patients, even when performed very early. Eculizumab, an antibody that inhibits complement factor 5a and the formation of the membrane attack complex, has recently been used in such cases and seems to provide a more specific therapeutic action. Control studies are needed to specify its use in this disease.

Thrombotic thrombocytopenic purpura (TTP) or Moschowitz syndrome: a true hematologic emergency

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by congenital or inherited disorders involving the processing of the ultra-large forms of von Willebrand factor. As a result, platelet-rich microthrombi form in the small arterial vessels of various organs, particularly those of the brain, heart, and kidneys. The idiopathic autoimmune form of TTP is the most common. There are various subgroups of acquired TTP associated with HIV infection, sepsis, pregnancy, autoimmune disease, various disseminated malignancies, and drugs. If not promptly treated, TTP is associated with high mortality, making it a true medical emergency. Materials and methods: The article is based on a review of the literature published between January and October of 2009. Its aim is to clarify the diagnosis, treatment, and follow-up of TTP. Results: Diagnostic criteria include the presence of microangiopathic hemolytic anemia associated with thrombocytopenia in the absence of other obvious causes. Assays of ADAMTS13 activity and titration of acquired antibodies against this enzyme are indicated in the follow-up of disease and as prognostic indicators. Treatment centers around daily plasma exchange associated with immunosuppressant drug therapy, particularly steroids and more recently the monoclonal anti-CD20 antibody rituximab. Discussion: Despite improved treatment, TTP is still associated with significant mortality (10—20%), particularly when plasma exchange is initiated late. Relapse also occurs in a substantial proportion of patients (10—40%) although the frequency of this outcome may be reduced by rituximab therapy.

A case of severe ADAMTS 13 deficiency presenting as thrombotic thrombocytopenic purpura in pregnancy

Thrombotic thrombocytopenic purpura is a rare life-threatening disorder characterized by thrombocytopenia and microangiopathic hemolytic anemia. It is caused by the absent or severe deficiency of the von Willebrand Factor-cleaving protease named ADAMTS13. Pregnancy is a well recognized factor precipitating the appearance of the disease both in women that had reduced levels of ADAMTS13 activity prior to gestation and in those with other inherited or acquired thrombophilic syndromes. We report a 25-year old woman with severe ADAMTS13 deficiency presented early in her 1st pregnancy and relapsed in two subsequent gestations. This presentation is uncommon for thrombotic thrombocytopenic purpura is associated with pregnancy (ADAMTS13 deficiency < 5%, without an inhibitor). In the first pregnancy she started with daily plasma exchange 1.5 x volume, corticosteroids and IV immunoglobulin and finally entered remission after 23 sessions and termination of pregnancy. In the second pregnancy she did not receive prophylactic treatment and relapsed in the 3rd trimester. Prophylactic treatment during the third pregnancy with plasma infusions proved also ineffective to prevent relapse. Many issues regarding treatment and prevention of thrombotic thrombocytopenic purpura relapses in subsequent pregnancies are unclear. Proposed guidelines recommend that the same treatment should be performed on pregnant and non pregnant patients without modification of plasma replacement dose according to ADAMTS13 levels. In addition, many authors suggest that pregnant patients with history of thrombotic thrombocytopenic purpura and severe deficiency of ADAMTS13 levels should received prophylactic treatment for prevention of relapses in the subsequent pregnancies. Severe ADAMTS 13 deficiency may present as thrombotic thrombocytopenic purpura of pregnancy. Pregnant women with thrombotic thrombocytopenic purpura and especially with severe deficiency of ADAMTS13 levels require specific consideration regarding treatment and prophylaxis in subsequent pregnancies.

Targeting B cells in severe thrombotic thrombocytopenic purpura–a road to cure?*

Targeting B cells in severe thrombotic thrombocytopenic purpura–a road to cure?*

Use of Anti-C5 Monoclonal Antibody Eculizumab in the Treatment of a Patient with Refractory Idiopathic Thrombotic Thrombocytopenic Purpura (TTP)

Abstract 4666 Background:Case reports and two prospective, controlled trials document the efficacy of anti-C5 monoclonal antibody eculizumab in the treatment of refractory atypical hemolytic uremic syndrome (aHUS) as well as in aHUS patients requiring chronic plasma exchange. It has shown efficacy in the presence and absence of defects in complement (C) and C regulatory proteins. However, eculizumab has not been previously used in TTP associated with low ADAMTS13 activity, despite the many shared clinical and pathologic features of TTP with aHUS. Case report:A 27 y.o. white male with a history of inflammatory bowel disease presented with fever, thrombocytopenia, and microangiopathic hemolytic anemia, and rapidly developed renal failure, seizures, and coma. ADAMTS13 activity was <5% of normal (IgG anti-ADAMTS13 inhibitor titer of 160), and LDH, 476 on presentation, steadily rose to 1321 by day 8 (Figure). Daily plasma exchange, initiated on hospital day 1, produced no improvement in platelet count, LDH, creatinine, schistocyte levels on peripheral blood smear, mental status, or seizure activity through day 8. Admission stress dose steroids were then increased to 60mg/day prednisone, and vincristine, N-acetylcysteine, and weekly rituximab infusions were initiated, with no change in clinical or laboratory status (Figure). Skin biopsies on day 21 revealed intense granular deposits of C3d, C4d, and the terminal membrane attack complex C5b-9 within and around vessels, including endothelium and pericytes, suggesting a role for local vascular C activation. Hence, eculizumab (900mg IV once a week for 4 weeks, with two supplemental weekly doses of 600mg to adjust for some loss of antibody with plasma exchange, and a final 1200mg dose) was added to the treatment regimen. Platelets increased to 71 and LDH declined to 293 by day 31, and ADAMTS13 activity normalized by day 54 (85%). Plasma exchange and eculizumab were discontinued, and a steroid taper initiated on day 56 when the platelet count was 213K, LDH 145, and creatinine 1.07. The beginning of a rapid decent in platelet count was noted on day 85, accompanied by a decrease in ADAMTS13 activity to 9%. Eculizumab alone (900mg) was restarted. Platelet count, Hb, and creatinine returned to normal within 9 days. Relevant clinical data:Figure and C1q and complement regulatory proteins: factors H, I, and B: normal. Outcome:In remission four months after initial presentation, receiving biweekly eculizumab infusions as an outpatient. Conclusion:Eculizumab was associated with remission induction in a patient with classic idiopathic TTP refractory to plasma exchange. Although multiple, overlapping initial therapies obfuscate assignment of efficacy to a single agent during initial treatment, remission obtained with eculizumab alone on relapse suggests its efficacy. Eculizumab should be considered in patients with refractory TTP. Eculizumab treatment is ongoing in this patient, but the duration of the treatment period remains to be elucidated. Our study also emphasizes that vascular C activation, possibly triggered by endothelial cell injury, may be a critical factor in at least some cases of TTP. C5b-9 induces a secretory response in endothelium to elaborate ultra high molecular weight von Willebrand factor multimers which would be ineffectually cleaved in patients with antibodies to ADAMTS13. This could lead to a dysregulated thrombotic microangiopathy. Blocking C5 formation may thus address a critical upstream pathway relevant to TTP as well as aHUS. Disclosures:Off Label Use:Eculizumab treatment of TTP is an off-label use. [Display omitted]

Long-term renal function under plasma exchange in atypical hemolytic uremic syndrome

Dear Sir, In a paper by Waters and Licht published recently in Pediatric Nephrology, eculizumab is presented as the emerging drug to replace plasma exchange (PE) to treat and prevent atypical hemolytic uremic syndrome (aHUS) [1], allowing complications possibly associated with chronic PE use related to arteriovenous fistula and infusion of blood products (viral infections, allergic reaction) to be avoided. Eculizumab is an anti-C5 monoclonal humanized mouse antibody that binds to C5 and prevents the action of C5 convertase that splits C5 in C5a and C5b, impeding formation of the C5b-9 membrane-attack complex (or MAC) that binds to and permeabilizes cell membranes, thereby killing microorganisms but also damaging host endothelial cells, as in aHUS. Eculizumab treatment has been shown to be successful in several reported aHUS cases. However, the use of this drug over the long term is limited by extremely high cost, possible infectious complications by Neisseria, and by fetal morbidity in case of administration during pregnancy. Although it has not yet been demonstrated, the possibility of developing antieculizumab antibodies cannot be excluded. Another recently proposed alternative to PE consists of combined kidney–liver transplantation, which remains, however, a high-risk procedure [1]. Because of the limitations of the latter techniques and the necessity of life-long treatment in a large number of cases, it seems important to us to emphasize the possibility that an adequate PE strategy could obtain long-term preservation of renal function in aHUS. In aHUS, CFH mutations are the most frequent. The prognosis in this group is poor, with most patients developing end-stage renal failure (ESRF) and a recurrence rate posttransplant of 80% [1] that, when not adequately treated, lead to graft loss in 100% of cases. Since our reports on successful aHUS treatment by intensive daily PE on native kidney and on kidney transplantation, followed by prophylactic PE pursued indefinitely and intensified during relapses [2, 3], this strategy has been widely recommended [4]. In this letter, we present the evolution of three sisters, two of whom are homozygote twins presenting with aHUS associated with CFH mutation (c.3572 C > T, Ser1191Leu) since data published in our previous paper [3]. These observations represent the longest successful prophylactic PE treatment used in aHUS. The oldest sister is more than 20 years old and received her third kidney transplant at the age of 17 under prophylactic PE initiated from before transplantation. Four months later, she experienced a severe relapse when the frequency of PE was reduced from two to one sessions per week. Immediate treatment by daily PE resulted in complete recovery of baseline renal function. Later on, due to severe reaction to plasma, PE had to be replaced with eculizumab treatment, which prevented HUS relapse and renal function deterioration (plasma creatinine 125 μmol/L 2 years after eculizumab initiation). Twin 1 [2, 3] presented an initial HUS episode at the age of 5 years. She reached ESRF 6 months later despite having received ten daily PE sessions initially and three courses of plasma infusion at the time of hematological exacerbation of the disease. She was transplanted with a cadaver kidney 2 years later under prophylactic PE (40 ml/kg of fresh frozen plasma) just before transplantation and then daily for 7 days, being progressively tapered and continued indefinitely once a week until now. Eight years posttransplantation, plasma creatinine was 145 μmol/L despite two relapses in the early posttransplantation period secondary to cytomegalovirus (CMV) infection, which responded well to daily PE sessions and ganciclovir. Twin 2 presented a first episode of HUS 6 months after her twin sister [3]. She was immediately treated with daily PE for 21 days until normalization of plasma creatinine and thereafter tapered to one session/2 weeks until now. Ten years after the first episode, plasma creatinine was normal (57 μmol/L), and the patient did not present any urinary abnormality. Long-term regular PE sessions did not worsen school performance and social life in that family. All three patients presented reactions to plasma that indicated in each case the use of Octaplas instead of fresh frozen plasma. Octaplas is a plasma preparation that considerably reduces reaction risk by assuming complete removal of cells and cell debris by multiple size-exclusion filtration steps. The latter product is also submitted to virus inactivation by S/D methods. In conclusion, in this family of patients with aHUS related to CFH mutation, intensive and prophylactic treatment with PE allowed long-term preservation of transplant and native renal function. However, because of the burden of this technique, the cost of eculizumab, and the high risk of liver transplantation, the best option for treating aHUS related to CFH mutation might be a human-plasma-derived CFH concentrate, presently being developed in France by the Laboratoire Francais du Fractionnement et des Biotechnologies.

Management of an acute outbreak of diarrhoea-associated haemolytic uraemic syndrome with early plasma exchange in adults from southern Denmark: an observational study

Diarrhoea-associated haemolytic uraemic syndrome in adults is a life-threatening, but rare multisystem disorder that is characterised by acute haemolytic anaemia, thrombocytopenia, and renal insufficiency. We aimed to assess the success of management of this disorder with plasma exchange therapy. Patients diagnosed with diarrhoea-associated haemolytic uraemic syndrome in southern Denmark were treated with daily plasma exchange by centrifugation and substitution with fresh frozen plasma. Stool culture and serological testing was done to identify the cause of disease, and the success of management with plasma exchange therapy was assessed from change in platelet count, glomerular filtration rate, and lactate dehydrogenase. During May 25-28, 2011, five patients with a median age of 62 years (range 44-70) presented with diarrhoea-associated haemolytic uraemic syndrome, which was caused by an unusual Shiga-toxin-producing Escherichia coli serotype O104:H4. Strains of E coli showed a high resistance to third-generation cephalosporins because the strains had extended-spectrum β lactamases. After plasma exchange, median platelet count and glomerular filtration rate increased, median lactate dehydrogenase concentration decreased, and neurological status improved. The time interval from onset of bloody diarrhoea to start of plasma exchange had an inverse correlation with reduction of lactate dehydrogenase concentrations by plasma exchange (p=0.02). All patients were discharged with normal neurological status at 7 days (range 5-8) after starting plasma exchange. Early plasma exchange might ameliorate the course of diarrhoea-associated haemolytic uraemic syndrome in adults. However, this finding should be verified in randomised controlled trials None.

Eculizumab for the Treatment of De Novo Thrombotic Microangiopathy Post Simultaneous Pancreas-Kidney Transplantation—A Case Report

A 34-year-old female recipient of a simultaneous pancreas–kidney transplant presented 7 days posttransplant with acute renal allograft dysfunction, thrombocytopenia, and microangiopathic hemolytic anemia. Renal biopsy revealed acute antibody-mediated rejection (AMR) and acute thrombotic microangiopathy (TMA). Clinical and laboratory manifestations, which had only partly responded to treatment with daily plasma exchange and intravenous immunoglobulin, resolved rapidly and completely to eculizumab (Soliris, Alexion Pharmaceuticals, Inc., Cheshire, Conn), a complement factor C5 antibody. De novo posttransplant TMA is a rare and serious complication that can lead to graft loss in up to one third of cases. This is the first report of successful treatment of de novo TMA with eculizumab, which has previously shown benefit in recurrent atypical hemolytic uremic syndrome as well as in refractory acute AMR. Targeted complement inhibition offers the promise of a safe and effective therapeutic strategy in de novo TMA, especially in light of recent evidence suggesting that genetic mutations in complement regulatory proteins may predispose transplant recipients to this serious disease.

Longitudinal Analysis of VWF Multimerization Patterns In a well-defined TTP Cohort

AbstractAbstract 4308VWF function has long been implicated in TTP's pathogenesis. Initial study reported unusually large (UL)VWF multimers in patients with relapsing TTP. Later, ULVWF were demonstrated in TTP patients during remission that are acutely consumed at the onset of disease. However, many detailed steps concerning the timely relationship between VWF multimerization and clinical courses such as disease onset, mortality, disease refractoriness, and treatment response are still missing. In this study, we performed VWF multimeric analyses in over 400 serial samples longitudinally collected from more than 20 TTP patients at various clinical stages, including initial presentation, acute treatment, clinical remission, and clinical visits prior to TTP relapses. At the time of acute presentation, approximately 50% of cases show presence of ULVWF multimer patterns, while around 35% demonstrate acute consumption of UL and high molecular weight VWF multimers. The other 15% of cases however reveal normal VWF multimer patterns at the time of disease presentation. For the TTP patients who normally respond to plasma exchange (PE) therapy, a mild ULVWF multimer pattern may be present after discontinuation of daily PE therapy. Upon restoration of ADAMTS13 activity and achievement of sustained remission, VWF multimer patterns are normalized. During the period of daily plasma exchange for acute episodes of TTP, a persistent presence of ULVWF multimer patterns appears indicative of disease refractoriness and is associated with disease mortality. In the course of this study, ADAMTS13 activity levels (reportable range of 0.5 % –100%) in these longitudinal samples were also precisely determined using SELDI-TOF mass spectrometry to establish the correlation between ADAMTS13 activity measured in vitro and VWF multimeric patterns formed in vivo. Our study for the first time defines the dynamic changes of VWF multimeric patterns in relation to the evolution and natural history of TTP in a large well-defined clinical cohort. These novel observations provide new implications into the pathobiology of TTP and may help to develop new biomarkers for monitoring therapeutic responses and for screening for TTP relapses. Disclosures:No relevant conflicts of interest to declare.

Circulating Nucleosomes Reflect Disease Activity in Patients with Thrombotic Microangiopathies.

AbstractAbstract 1437 Background:Thrombotic microangiopathies (TMAs) including thrombotic thrombocytopenic purpura (TTP) associated with acquired or congenital severe ADAMTS13 deficiency, typical diarrhea-associated (D+) and atypical (D-) hemolytic uremic syndrome (HUS), and other TMAs associated with disseminated neoplasia, some drugs, pregnancy and several infectious or autoimmune conditions are life-threatening diseases characterized by microvascular thrombosis with organ dysfunction, consumptive thrombocytopenia and hemolytic anemia with red blood cell fragmentation. Severe autoantibody-induced ADAMTS13 deficiency is found in about 60% of patients diagnosed with acquired TTP and severe constitutional ADAMTS13 deficiency due to ADAMTS13 mutations is found in almost all patients with hereditary TTP. However, some patients with severe acquired or hereditary ADAMTS13 deficiency may be asymptomatic for prolonged time intervals and some triggering factor(s) may be needed to bring about acute disease. Extracellular exposure of DNA and histones is a recently discovered mechanism linking inflammation with thrombosis. Chromatin fibers released from activated neutrophils (Neutrophil Extracellular Traps, NETS) bind platelets, erythrocytes and DNA/histone complexes stimulate platelet aggregation and coagulation. We investigated stored plasma samples from patients with various forms of TMA, both during acute disease and during remission, for circulating nucleosomes, i.e. subunits of chromatin composed of DNA wrapped around a histone core. Patients:First, 29 patients with acute TMA (6 acquired TTP with severe ADAMTS13 deficiency, 4 D+ HUS, 8 neoplasia-associated TMAs and 11 TMAs of undetermined etiology) were investigated and compared to 10 healthy controls. Second, serial samples from 8 patients with TTP and acquired ADAMTS13 deficiency obtained during acute disease, during plasma exchange (PE) treatment and during remission were analyzed as were samples from 3 hereditary TTP patients during acute disease and during remission. Methods:Plasma DNA was quantified, nucleosomes were measured using an antibody against DNA complexed with histones H2A/H2B. Plasma lactate dehydrogenase and myeloperoxidase were assayed using commercial kits. Results:Significantly elevated levels of DNA and histones organized in nucleosomes were found in patients with acute TMAs. Increase in nucleosome levels was paralleled by elevation of plasma myeloperoxidase and calgranulin pointing to neutrophils as the origin of nucleosomes. All patients achieving clinical remission from acute acquired TTP showed normalized levels of nucleosomes indistinguishable from those in healthy controls. Transient disease flare-ups with worsening platelet counts in acute acquired TTP patients subjected to daily PE therapy were often associated with a transient increase of the nucleosome levels. One patient who died after 10 days of PE had extremely high nucleosome levels prior to death. Three patients with hereditary severe ADAMTS13 deficiency had variably elevated nucleosome levels during active disease and normal levels in remission maintained by regular plasma infusion (n=2) or mildly increased levels in remission without maintenance plasma therapy (n=1). Conclusion:Circulating nucleosomes may reflect the degree of systemic inflammation and seem – at least in some cases - to reflect the second hit precipitating acute disease in patients at risk for acute TMA, such as those with acquired or hereditary severe ADAMTS13 deficiency. Disclosures:Kremer Hovinga:Baxter Bioscience: Consultancy. Lämmle:Baxter Bioscience: Consultancy.

Schwerste thrombotisch-thrombozytopenische Purpura (TTP) nach H1N1-Vakzinierung

Thrombotic thrombocytopenic purpura (TTP) is a severe disease with microthrombi in various organs. The idopathic subtype is characterized by reduced ADAMTS13 activity mediated via autoantibodies against this protease. Induction of autoantibodies mechanistically is incompletely understood, but certain drugs can induce anti-ADAMTS13 antibodies through hapten mechanisms. A 56-year-old man was admitted from an external hospital because of a rapidly worsening general condition, hemolytic anemia (hemoglobin 4.17 mmol/l, hematocrit 0.19), and thrombocytopenia (22 Gpt/l) for unknown reasons. Additionally, he was found to have an elevated lactate dehydrogenase (45.37 μmol/l/s). 13 days before hospitalization he had received vaccination against H1N1. Laboratory tests revealed an increased total bilirubin (126 μmol/l), and a decreased haptoglobin level (< 0.08 g/l). The blood smear showed 24% fragmentocytes. Direct and indirect Coombs test were negative. TPP was diagnosed based on the clinical presentation and the detection of ADAMTS13 antibodies. Despite daily plasma exchange via plasmapheresis and administration of corticosteroids, there was no significant rise in platelet counts. Immunosuppression with a total of four weekly doses of rituximab (375 mg/m(2) body surface area) was added. Over the next 5 weeks, the platelet count very slowly rose. After a total of 46 sessions, plasmapheresis was ended with complete remission of the disease. This report emphasizes the immunologic susceptibility of TTP, and suggests the potential, but not proven role of H1N1 vaccination in the pathogenesis of TTP, because no serum before vaccination was available. Severe autoantibody TTP can be successfully treated by administering rituximab in addition to standard treatment with plasmapheresis and corticosteroids.

Porpora trombotica trombocitopenica (PTT) o sindrome di Moschowitz: una vera urgenza ematologica

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by congenital or inherited disorders involving the processing of the ultra-large forms of von Willebrand factor. As a result, platelet-rich microthrombi form in the small arterial vessels of various organs, particularly those of the brain, heart, and kidneys. The idiopathic autoimmune form of TTP is the most common. There are various subgroups of acquired TTP associated with HIV infection, sepsis, pregnancy, autoimmune disease, various disseminated malignancies, and drugs. If not promptly treated, TTP is associated with high mortality, making it a true medical emergency. The article is based on a review of the literature published between January and October of 2009. Its aim is to clarify the diagnosis, treatment, and follow-up of TTP. Diagnostic criteria include the presence of microangiopathic hemolytic anemia associated with thrombocytopenia in the absence of other obvious causes. Assays of ADAMTS13 activity and titration of acquired antibodies against this enzyme are indicated in the follow-up of disease and as prognostic indicators. Treatment centers around daily plasma exchange associated with immunosuppressant drug therapy, particularly steroids and more recently the monoclonal anti-CD20 antibody rituximab. Despite improved treatment, TTP is still associated with significant mortality (10–20%), particularly when plasma exchange is initiated late. Relapse also occurs in a substantial proportion of patients (10–40%) although the frequency of this outcome may be reduced by rituximab therapy.

CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency

CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency

Efficacy of Eculizumab in the Treatment of Recurrent Atypical Hemolytic-Uremic Syndrome After Renal Transplantation

Efficacy of Eculizumab in the Treatment of Recurrent Atypical Hemolytic-Uremic Syndrome After Renal Transplantation

TTP disease course is independent of myeloma treatment and response

TTP disease course is independent of myeloma treatment and response

Clinical applications of therapeutic apheresis

The vast majority of the renal indications for plasmaexchange are related to immunoglobulin removal.Immunoglobulins, especially IgG, have a relativelylong half-life. Thus in antibody-mediated disease, therecould be persistence of significant amounts of antibodyin the circulation despite cessation of antibody produc-tion. The aim of plasma exchange is to significantlyreduce circulating antibodies. Removal of the circulat-ing antibodies constitutes the rationale for using plas-mapheresis to treat antibody-associated glomeruloneph-ritis (GN). Although small molecular weight substancesare removed by plasma exchange, their large volumeof distribution and short half-lives make plasmaexchange an inefficient means of extracorporeal re-moval of these substances. For instance, some comple-ment proteins have a half-life of 2 days. If the goalwere to be to deplete plasma complement levels, virtu-ally daily plasma exchanges would be needed. Discon-tinuation of daily plasma exchange would be followedby rapid resurgence to normal complement titers.Hence the shorter the half-life of the molecule beingremoved, the more aggressive has to be the apheresisschedule.Plasma volume can be estimated using the followingformula:EPV ¼ 0:065 3 TBW 3 ½1 Hctwhere EPV is the estimated plasma volume, TBW isthe total body water, and Hct is hematocrit.The removal of large molecular weight substancesfrom the plasma compartment follows first-orderkinetics. Repetitive treatments should be spaced every24–48 h to allow for extravascular to intravascularequilibration.Apheresis has been used to treat several renal condi-tions including primary renal diseases as well as renalmanifestations of systemic conditions (Table I).

Influenza A Infection Triggers Thrombotic Thrombocytopenic Purpura by Producing the Anti-ADAMTS13 IgG Inhibitor

A 68-year-old Japanese woman infected with influenza A developed thrombotic thrombocytopenic purpura (TTP) 2 days after having a fever. Routine laboratory tests on admission suggested a diagnosis of disseminated intravascular coagulation. However, ADAMTS13 assays showed an extremely low level of plasma ADAMTS13 activity with a high titer of anti-ADAMTS13 inhibitor (IgG). Despite high-dose methylprednisolone therapy with daily plasma exchange for 3 consecutive days, the patient died of pulmonary congestion complicated by cardiac failure. Our experience here provides the first evidence that influenza A infection is sufficient to trigger TTP by producing the anti-ADAMTS13 IgG inhibitor.

Therapeutic plasma exchange reveals a color‐coordinated response to cyclosporine‐induced microangiopathic hemolytic anemia and rifampin after stem cell transplant

A 39 year old woman with T/NK-cell lymphoma developed microangiopathic hemolytic anemia (MAHA) associated with cyclosporine A (CSA) toxicity 15 days after allogeneic peripheral blood stem cell transplantation. Her serum creatinine level increased from 0.4 mg/dL pre-transplant to 1.0 and 2.9 mg/dL on days 9 and 15 post-transplant, respectively, leading to cessation of CSA therapy. Peripheral blood smears revealed a dramatic increase in schistocytes (4 per high-power field) on day 14. LDH levels rose from 708 to 4103 U/L on post-transplant days 1 and 15, respectively. Declining hemoglobin concentration and platelet count were attributed initially to the transplant rather than to evolving MAHA. Because of her critical condition, a 5-day course of daily therapeutic plasma exchange (TPE) was initiated as an extreme measure. Plasma removed during the 1st TPE (Figure 1) illustrates the classic tea-color associated with MAHA. During the first 3 days of TPE, CSA levels were 113, 95, and 106 mcg/L. Rifampin, a potent inducer of cytochrome 450 3A4, was administered on days 18 and 19 to promote clearance of CSA. Rifampin stains body fluids a characteristic orange-red color, noted in the plasma removed during the 4th TPE (Figure 2). Plasma color returned to clear yellow by the final day of TPE (Figure 3). Creatinine levels peaked at 4.6 mg/dL on day 19. CSA and creatinine levels declined to 48 mcg/L and 3.4 mg/dL, respectively, the day following completion of TPE and rifampin administration, and further decreased to 34 mcg/L and 1.6 mg/dL 2 days later. Figure 1 Plasma removed during first TPE demonstrating classic tea-colored plasma associated with MAHA. Figure 2 Orange-red plasma removed during fourth TPE after administration of rifampin to promote clearance of CSA. Figure 3 Clear yellow plasma removed during fifth and final TPE procedure.

Berend Houwen Memorial Lecture: ISLH Las Vegas May 2009

Thrombotic microangiopathies are a relatively rare group of congenital and inherited disorders caused by defects in processing the ultra large forms of von Willibrand factor which pathologically give rise to platelet rich microthrombi in the micro arterial circulation leading to end organ damage particularly in the brain, heart and kidneys. Identification of the ADAMTS 13 gene has led to the definition of congenital deficiency of its activity or failure of activity due to the development of an inhibitory IgG antibody. The idiopathic autoimmune form of the disease is the most common. There are various subgroups of acquired TTP associated with HIV infection, pregnancy, pancreatitis, associated with bone marrow transplantation, various disseminated malignancies and certain drugs, particularly Clopidogrel. Diagnostic assays are now becoming widely available to identify ADAMTS 13 activity and also acquired antibodies to the enzyme. Mainline treatment is associated with daily plasma exchange with associated other immunosuppressant treatments particularly steroids and recently the use of Rituximab, a monoclonal anti- CD20 antibody. Despite improvement in treatment modalities there is still significant mortality of 10-20%, particularly if there is a delay in initiating plasma exchange. Relapse also occurs in 20-50% of patients although this may be improved by Rituximab therapy.