ASFA Category IV becomes Category I: Idiopathic thrombotic thrombocytopenic purpura in a patient with presumed gemcitabine‐induced thrombotic microangiopathy

In the implementation of American Society for Apheresis national guidelines, the decision for therapeutic plasma exchange may be confounded by a clinical presentation that fits both a Category I and IV designation. We report the case of a 45‐year‐old female who presented with concern for a Category IV disorder, gemcitabine‐induced thrombotic microangiopathy, and was ultimately diagnosed with a Category I disorder, idiopathic thrombotic thrombocytopenic purpura. This case highlights the importance of ruling out idiopathic TTP by a thorough evaluation for ADAMTS13 activity and inhibitor, even when an alternate thrombotic microangiopathy diagnosis may be likely.     

Therapeutic apheresis in neurological disorders: a survey of the evidence in support of current category I and II indications for therapeutic plasma exchange

Neurologic disorders constitute the largest group of indications for therapeutic plasma exchange. Although some of the traditional indications are supported by properly designed randomized trials, others are not. This article provides a critical look at the evidence in support of the assignment by ASFA of Category I or II indications to neurologic disorders in its most recent (2007) evaluation of therapeutic apheresis.     

Simple "closed-circuit" group-specific immunoadsorption system for ABO-incompatible kidney transplants.

There is a need for improvement of the detection and treatment of the antibody-mediated graft rejection for ABO-incompatible kidney transplant recipients. With the development of novel pre-conditioning protocols, which employ anti-CD20 antibody, therapeutic plasma exchange plus extracorporeal immunoadsorption and standard immunosuppression application, together with the use of more sensitive and objective assays for immunological monitoring, patients that were not candidates for kidney transplant in the past, are now being transplanted. We have designed a pre-conditioning protocol for ABO-incompatible kidney transplants based on TPE plus our own simple "closed-circuit" immunoadsorption technique - combined by anti-CD20, standard immunosuppressive treatment, and without splenectomy. The results obtained in this study strongly support our hypothesis leading to the conclusion that this protocol can be used successfully, with high-quality ABO antibody depletion (p<0.001) and beneficial clinical findings. The application of this protocol is safe, and not associated with alteration in normal plasma constituent levels or with occurrence of any side effects of apheresis or clinical consequences. Finally, this pre-conditioning protocol radically reduces the treatment-cost. Definitive conclusions can only be drawn from larger, randomized, controlled clinical trials.     

Indications for therapeutic plasma exchange at a university hospital and a regional blood center

The AABB guidelines for therapeutic plasma exchange (TPE) are divided into four categories: I. TPE is "standard and acceptable therapy," II. "generally accepted," III. "insufficient evidence to evaluate efficacy," and IV. "data suggest no therapeutic efficacy." Since little is known about the implementation of these guidelines, and since the indications for TPE may vary, depending upon an institution's patient mix, this study reviewed the indications and their categories for two co-located institutions. A retrospective review of the indications for all patients undergoing TPE from January 1, 1994 to December 31,1997 at Emory University Hospital (EUH), a tertiary-care teaching hospital, and the American Red Cross (ARC), a regional blood center, using AABB criteria (ASFA criteria used when not rated [NR] by AABB) was conducted. Categories I/II represented 75% and 88% of cases (EUH and ARC, respectively), while Categories III/IV/NR (NR as used below is "not rated" by both AABB and ASFA criteria; n is number of patients) were 25% and 12% of indications, respectively (P =0.002). Cases at EUH (n=101) were I, 62%; II, 13%; III, 3%; IV, 13%; and NR, 9%. Cases at ARC (n=359) were I, 77%; II, 11%; III, 9%; IV, 0%; and NR, 3% (P<0.001). No Category IV patients underwent TPE at ARC (13% at EUH). Thrombotic thrombocytopenic purpura (TTP) was the most common indication for TPE at both centers. The majority of the procedures were "appropriate" (Categories III/); several disorders ( approximately 10%) for which TPE was utilized at both centers were NR by both AABB and ASFA guidelines. Indications for TPE may differ, depending on the type of requesting institution. Physicians requesting TPE for patients with disorders in Categories III/IV/NR should be more strongly encouraged to enter their patients into controlled trials to best evaluate the efficacy of TPE in inadequately-studied clinical situations. This might best be accomplished at university hospitals, where requests for Category III/IV/NR may be higher. A need exists for periodic updating of the AABB guidelines to include those diseases for which new information is available with regard to the potential therapeutic role of TPE.     

Therapeutic plasma exchange in refractory Susac's syndrome: A brief report

Susac's syndrome (SuS) is an autoimmune endotheliopathy that typically presents with the clinical triad of encephalopathy, hearing loss, and branch retinal artery occlusion. It has a wide range of possible presentations, and its pathogenesis remains uncertain. Fulminant and refractory cases are difficult to treat, and no standard treatment protocol has been established. However, therapeutic plasma exchange (TPE) has been described as an adjunctive therapy in several SuS cases. Herein we present a case of a 63-year-old male with debilitating encephalopathy and recent hearing and vision loss, who responded favorably to TPE. Given this and other published reports of plasma exchange therapy for SuS, treatment protocols should consider TPE in early stages of disease.     

Therapeutic apheresis: Results from a single center in Turkey.

BACKGROUND: Therapeutic apheresis (TA) is carried out for a broad spectrum of diseases and syndromes. AIM: We retrospectively evaluated the results of therapeutic apheresis (TA) including plasma exchange, therapeutic plateletpheresis, and leukapheresis during 2000-2006. METHODS: A total of 195 procedures were performed in 44 patients (25 male and 19 female, with a mean age of 52+/-15 years). These procedures consist of 165 plasma exchanges, 20 therapeutic plateletpheresis, and 10 leukapheresis. The most common indications were hematological, neurological, and metabolic diseases. Eighty-three percent of plasma exchange, 100% of plateletpheresis and leukapheresis belonged to indication Category I or II, according to the guidelines of the American Society for Apheresis. RESULTS: While hemoglobin levels significantly increased (p<0.05), platelet counts decreased (p<0.005) after plasma exchange. Hematological parameters did not statistically change significantly with leukapheresis (p>0.05). Platelet counts significantly decreased with plateletpheresis (p<0.001). Total complications were detected in 21% of the procedures. Adverse events (AE) were seen in 17% of the procedures. None of the patients died (Grade-IV) from any complication. AEs occurred in 14% (Grade-I), 1% (Grade-II), and 2% (Grade-III) of the procedures. The most common AEs were nausea/vomiting, hypotension, and abdominal pain. CONCLUSION: TA, an important procedure in Transfusion Medicine, is safely carried out in our center in several hematological, neurological, and metabolic diseases which are similar to previous reports.     

Prognostic markers in prostate cancer

In this review, a series of relatively well-documented ancillary biomarkers and emerging molecular assays are evaluated for their relative ability to predict prognosis in prostate cancer. Prognostic factors that have achieved widespread use and classified as Category I by the College of American Pathologists Solid Tumor Prognostic Factor Consensus Conference are compared with newer tests that are beginning to be used in clinical practice (Category II) and emerging molecular-based assays that have yet to be widely validated in the published literature or clinical trials (Category III).     

Plasma exchange and prednisone in acute inflammatory polyradiculoneuropathy: a controlled randomized trial

A controlled-randomized trial of plasma exchange combined with prednisone was compared to supportive care alone in patients with acute inflammatory polyradiculoneuropathy (AIP). The design of this study differs from other reported trials of plasma exchange in AIP because prednisone was used in the treatment group to prevent the possibility of antibody rebound. Furthermore, in this study, detailed muscle strength testing formed the principal basis for assessment of therapeutic efficacy while in the British, North American, and French studies, a functional assessment scale was used. Analysis of our data revealed no significant improvement in the treated group over the controls. The sample size, albeit small (12 treated and 13 controls), had the power (95% chance) to detect a change of two British Medical Research Council grades of strength between the groups. The difference in our results versus others (North American and French studies) probably reflects the adverse effects of prednisone on recovery in AIP. An additional consideration is that plasma exchange may have an overall modest effect on the course of AIP, less appreciated when individual muscles are tested compared to assessment by large functional categories.     

Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome: what is the treatment?

ABSTRACT: INTRODUCTION: Hyperferritinemia is associated with increased mortality in pediatric sepsis multiple organ dysfunction syndrome (MODS), and critical illness. The International Histiocyte Society has recommended that children with hyperferritinemia and secondary hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) should be treated with the same immunosuppressant/cytotoxic therapies used to treat primary HLH. We hypothesized that patient with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS can be successfully treated with a less immunosuppressant approach than is recommended for primary HLH. METHODS: Multi-center cohort study of children in Turkish Pediatric Intensive Care units with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS treated with less immunosuppression (plasma exchange and intravenous immunoglobulin or methyl prednisolone) or with the primary HLH protocol (plasma exchange and dexamethasone or cyclosporine A and/or etoposide). The primary outcome assessed was hospital survival. RESULTS: 23 children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS were enrolled (median ferritin = 6341 g/dL, median number of organ failures = 5). Univariate and multivariate analyses demonstrated that use of plasma exchange and methyl prednisolone or intravenous immunoglobulin (n=17, survival 100%) was associated with improved survival compared to plasma exchange and dexamethasone and/or cyclosporine and/or etoposide (n = 6, survival 50%) (P = 0.002). CONCLUSIONS: Children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS can be successfully treated with plasma exchange, intravenous immunoglobulin, and methylprednisone. Randomized trials are required to evaluate if the HLH-94 protocol is helpful or harmful compared to this less immune suppressive and cytotoxic approach in this specific population.     

Thrombotic thrombocytopenic purpura: 24 years of experience at the American University of Beirut Medical Center

Thrombotic thrombocytopenic purpura (TTP) is a hematological syndrome defined by the presence of thrombocytopenia and microangiopathic hemolytic anemia without a clinically apparent etiology. Patients may also suffer from fever in addition to neurological and renal impairment. Treatment should be initiated as soon as possible, otherwise this rare disease can be fatal. The main treatment options include therapeutic plasma exchange, fresh frozen plasma infusion, and adjuvant agents such as steroids and antiplatelet drugs. A search of patient records was carried out at the American University of Beirut Medical Center looking for patients who developed TTP over a 24-year period extending from 1980 to 2003. Relevant information was collected and analyzed. A total of 47 records were found. All presented with anemia and thrombocytopenia, 83% had neurological symptoms, 61.7% had fever and 34% had renal impairment. All patients were treated with a multimodality regimen including therapeutic plasma exchange, FFP infusion, steroids, antiplatelet agents, vincristine and others. 38 (81%) cases achieved complete remission. Out of these, 12 (31.6%) relapsed and responded to treatment. Patients who did not receive plasma exchange were more likely to relapse (P = 0.032). A second relapse was observed in 6 cases. The overall mortality rate from TTP over 24 years was 21.3%. TTP remains a fatal disease. A high index of suspicion should, therefore, always be present. Treatment options should be further developed and patients should directly be referred to tertiary care centers.     

Management of atrial fibrillation: What is new in the 2014 ACC/AHA/HRS guideline?

Recently, the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society published an updated guideline on the management of atrial fibrillation (AF). This document is a complete revision of the 2006 guideline. Prominent changes in the 2014 guideline include the use of the CHA₂DS₂-VASc score for risk stratification of stroke, recommendations on when and how to use newer oral anticoagulants for thromboprophylaxis, downgrading of the use of aspirin for thromboprophylaxis of moderate-risk patients, and the use of catheter ablation in selected patients as first-line therapy for paroxysmal AF. In regard to rate control, the 2014 guideline reverts back to a previous recommendation for stricter targets for mean and maximum heart rate on therapy. The current guideline incorporates many recent trials in updating existing recommendations from the 2006 guideline. The 2014 guideline will be a vital tool in guiding physicians in the management of AF.     

Adjunct therapeutic plasma exchange for anti-N-methyl-D-aspartate receptor antibody encephalitis: a case report and review of literature

Encephalitis associated with autoantibodies directed against the N-methyl-D-aspartate receptor (NMDAR) is usually a paraneoplastic syndrome that presents in young females with ovarian teratomas. We report a case of a previously healthy 14-year-old girl with sudden-onset paranoia, hallucinations, hyperactivity, increased speech, decreased sleep, seizures, and violent behavior deteriorating to catatonia. Her cerebrospinal fluid tested positive for anti-NMDAR antibodies. She was treated with five sessions of therapeutic plasma exchange (TPE) after having failed therapy with antibiotics, intravenous steroids, intravenous immunoglobulin (IVIG), one dose of rituximab, and seven sessions of electroconvulsive therapy (ECT). The American Society for Apheresis assigns a Category III (Grade 2C) recommendation for TPE in paraneoplastic neurologic syndromes; however, apheresis specifically for anti-NMDAR encephalitis has not been well studied. Literature review revealed two case reports describing outstanding improvement in patients with anti-NMDAR encephalitis following TPE. We report no improvement in our patient's symptoms after plasma exchange and discuss possible reasons for why it failed along with review of the literature.     

Plasma exchange in neurological diseases

The objective of therapeutic plasma exchange' is to remove plasma from toxic substances, either autoantibody, alloantibody, immune complex, monoclonal protein or toxin. Plasma exchange can also act through replenishment of a specific plasma factor. Pathophysiology was the first rationale for the use of plasma exchange. Its first indication was indeed the hyperviscosity syndrome,¹ on the single basis of pathogenesis. However, pathogenesis alone does not convince physicians to use such a costly and potentially unsafe treatment. Therefore, randomized clinical trials have been conducted for the last 15 years to ascertain the effectiveness and tolerance of plasma exchange, especially in neurological diseases.In myasthenia gravis, the recommended use of plasma exchange was mainly based on the theoretical argument of elimination of anti-acetylcholine receptor antibodies. However, even if clinical improvement was observed after plasma exchange, this was also observed in myasthenia gravis associated with no circulating antibodies.In contrast, numerous randomized clinical trials have been initiated in the Gullain-Barré syndrome, although the pathogenesis of the disease is unknown. Nevertheless, the large number of trials assessing plasma exchange in the last 15 years, especially in neurological diseases, explains the increased indications for plasma exchange in the national base of the French register of plasmapheresis.²The demonstrated clinical benefit of plasma exchange through randomization may be an initial step in the understanding of disease. Plasma exchange probably does not simply act through removal of toxic substances, but also, as high doses of intravenous immune globulins,³ through immunomodulation. This could at least explain the competition and the complementarity of these two treatments.The objective of this paper is to present the main indications for plasma exchange in neurological diseases, complementing the conclusions of the consensus conference that met in 1996.⁴ We focus on the assessments through randomized clinical trials, though uncontrolled studies in rare diseases are also reported.     

The management of anticoagulation in patients undergoing therapeutic plasma exchange: A concise review

We surveyed multiple apheresis centers represented by the authors for their clinical approach to the management of anticoagulation issues during therapeutic plasma exchange (TPE). We present the results of their practices and a review of the pertinent literature. As plasma is removed during TPE, replacement with all or partial non‐plasma‐containing fluids (eg, 5% albumin) may lead to significant changes in hemostasis. These changes are amplified in patients who are receiving anticoagulation. We discuss various anticoagulants as well as the monitoring and adjustment of anticoagulation before, during, and after TPE. No single guideline can be applied, but rather, patients must be monitored individually, taking into account their often complex clinical conditions and medication profiles.     

Immunoadsorption in neurological disorders

In recent years, immunoadsorption has been increasingly recognized as an alternative to therapeutic plasma exchange and used for the treatment of neurological disorders such as Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, neuromyelitis optica spectrum disorders, and multiple sclerosis, as well as autoimmune encephalitis. Unlike therapeutic plasma exchange, which requires fluid replacement with a blood solution such as fresh frozen plasma or albumin, immunoadsorption is a blood purification technique that enables the selective removal of humoral factors from separated plasma through a high-affinity adsorbent with tryptophan or phenylalanine. Although the mechanisms underlying the therapeutic effects of immunoadsorption treatment remain to be fully elucidated, they are based on the removal of pathogenic humoral factors from circulating blood, such as disease-specific autoantibodies, complement, and inflammatory cytokines. The American Society for Apheresis has published evidence-based guidelines on the use of therapeutic apheresis in clinical practice, with specific instructions on 16 neurological disorders. However, the modality recommended in the guidelines for most of these disorders is therapeutic plasma exchange. This part of our review focuses on the clinical aspects of immunoadsorption. We also describe the efficacy of immunoadsorption and the evidence obtained by previous studies of the treatment of neurological disorders. Immunoadsorption could greatly improve the treatment of patients with autoimmune neurological disorders but further evidence is needed to confirm the efficacy of immunoadsorption in clinical practice.     

A 43-year-old woman with unexplained elevation of hCG

ObjectiveThis case report investigates an unusual hCG result in a woman who is not pregnant.Patient and methodsA 43-year-old woman was admitted for recurrence of thrombotic thrombocytopenic purpura (TTP) and therapeutic plasma exchange (TPE) was initiated. Prior to transitioning the patient from TPE to immunosuppressive therapy, a serum qualitative hCG test was performed and was positive. Several etiologies for elevated hCG were considered and investigated, including heterophile antibody interference, endogenous hCG from pituitary or malignancy, and exogenous hCG.ResultsRetrospective measurement of hCG levels in remnant samples, including a sample obtained prior to TPE initiation, demonstrated that the hCG elevation occurred with plasma administration for TPE. Further investigation with the American Red Cross confirmed that a plasma donor was unknowingly pregnant and in the latter half of the first trimester at the time of donation, when hCG levels peak.ConclusionIn plasma recipients with unexplained hCG elevation, passive transfer of hCG from plasma should be considered in the differential diagnosis. Retrospective measurement of hCG in remnant samples obtained prior to plasma exchange can assist in confirming the source.     

Efficacy of therapeutic plasma exchange in a patient with coagulation inhibitors (acquired haemophilia A) – A case report

Acquired haemophilia A (AHA) is a rare disorder with mostly idiopathic aetiology that leads to factor VIII (FVIII) deficiency due to coagulation inhibitors formation. Treatment protocol includes immunosuppression and Factor VIII bypassing agents including activated Prothrombin Complex Concentrates (PCC). Nevertheless, the role of plasma exchange is not clear in the treatment of AHA. We report a case of 73 year old male who presented with haematuria, prolonged activated partial thromboplastin time (APTT) and a very high titres of Factor VIII inhibitors of 98 Bethesda units (BU) and was diagnosed with acquired haemophilia A. He failed to respond to multiple immunosuppressive therapies including rituximab. Therefore, therapeutic plasma exchange (TPE) therapy was planned due to persistence of haematuria despite immunosuppressive therapies. After five cycles of plasma exchange, APTT became normal, haematuria subsided and Factor VIII inhibitors became negative. Patient was discharged without any bleeding and in a stable condition. In this index case, plasma exchange played a very crucial role, resulting in recovery of the patient. These results advocate that therapeutic plasma exchange is an effective therapy for acquired haemophilia A.     

Are all therapeutic plasma preparations the same: Is it worth assessing them in clinical trials?

Contrary to what is generally considered, plasma for direct therapeutic use is all but “standard” and can be made using a multitude of variable processes differing from one preparation to another; in sum, those changes make the final component inhomogeneous especially within inter-blood bank comparisons. The variability is further multiplied by the donors’ genetic polymorphisms. This is rarely addressed in the clinical trials and meta analyses, though this may have impact on clinical outcome in patients. This short review encompasses the variability parameters in the processing of therapeutic plasma and advocates for novel, prospective, trials to assess which type of plasma is the most beneficial to patients in need, as this type may differ depending on the patients’ pathological condition.     

The choice of the intravenous fluid influences the tolerance of acute normovolemic anemia in anesthetized domestic pigs

Introduction

Hyperferritinemia is associated with increased mortality in pediatric sepsis, multiple organ dysfunction syndrome (MODS), and critical illness. The International Histiocyte Society has recommended that children with hyperferritinemia and secondary hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) should be treated with the same immunosuppressant/cytotoxic therapies used to treat primary HLH. We hypothesized that patients with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS can be successfully treated with a less immunosuppressant approach than is recommended for primary HLH.

Methods

We conducted a multi-center cohort study of children in Turkish Pediatric Intensive Care units with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS treated with less immunosuppression (plasma exchange and intravenous immunoglobulin or methyl prednisolone) or with the primary HLH protocol (plasma exchange and dexamethasone or cyclosporine A and/or etoposide). The primary outcome assessed was hospital survival.

Results

Twenty-three children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS were enrolled (median ferritin = 6341 ??g/dL, median number of organ failures = 5). Univariate and multivariate analyses demonstrated that use of plasma exchange and methyl prednisolone or intravenous immunoglobulin (n = 17, survival 100%) was associated with improved survival compared to plasma exchange and dexamethasone and/or cyclosporine and/or etoposide (n = 6, survival 50%) (P = 0.002).

Conclusions

Children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS can be successfully treated with plasma exchange, intravenous immunoglobulin, and methylprednisone. Randomized trials are required to evaluate if the HLH-94 protocol is helpful or harmful compared to this less immune suppressive and cytotoxic approach in this specific population.     

Effect of plasma exchange on refractory hemophagocytic syndrome complicated with myelodysplastic syndrome.

A case of hemophagocytic syndrome (HPS) refractory to corticosteroid therapy was successfully treated by plasma exchange. The patient was a 56-year-old woman who had undergone regular hemodialysis for 10 years for complicated myelodysplastic syndrome (MDS) and then had had lung tuberculosis. After the onset of tuberculosis, she suffered from HPS and was treated by antituberculosis agents and high dose corticosteroid administration without any effect on the HPS. After adding a series of plasma exchanges, the HPS improved gradually, and her MDS began to respond to corticosteroid therapy. Plasma hypercytokinemia due to HPS was corrected by plasma exchange, and the correction of a high level of plasma inflammatory cytokine was considered to be one of the contributing factors for the improvement of HPS. These results suggest that therapeutic plasma exchange should be considered as a therapeutic tool for HPS refractory to conventional therapy.