Constance Danielson

Therapeutic leukapheresis in hyperleucocytic leukaemias: lack of correlation between degree of cytoreduction and early mortality rate

The clinical and laboratory data of 48 leukapheresis‐treated patients with hyperleucocytic leukaemia (HL) was reviewed to assess the correlation between the degree of leucoreduction and early mortality. Leukapheresis resulted in > 50% leucoreductions and postapheresis WBC counts <100 × 109/l in most patients (64.5%). Patients presenting with neurological, respiratory or renal complications had higher early mortality rates than patients without such complications, despite similar initial WBC counts and comparable leucoreductions. Thus, in these patients, more efficient leucoreduction was not associated with improved early survival.

Ticlopidine-, clopidogrel-, and prasugrel-associated thrombotic thrombocytopenic purpura: A 20-year review from the southern network on adverse reactions (SONAR)

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.

Pulmonary pathology of rapidly fatal transfusion-related acute lung injury reveals minimal evidence of diffuse alveolar damage or alveolar granulocyte infiltration.

BACKGROUND: Transfusion‐related acute lung injury (TRALI) is the leading cause of transfusion‐associated death in the United States. Its diagnosis is based on clinical and radiographic changes that are indistinguishable from acute lung injury/acute respiratory distress syndrome (ALI/ARDS). TRALI is presumed to be a form of ALI/ARDS; however, it differs in its triggering events and associated mortality. Two cases of rapidly fatal TRALI in which the postmortem pathology differed from that classically associated with ALI/ARDS are reported.

Thrombotic Thrombocytopenic Purpura: Yesterday, Today, Tomorrow

Abstract:  Although much has been learned about the pathophysiologic process of thrombotic thrombocytopenic purpura (TTP), both diagnostically and therapeutically, since its initial description by Moschcowitz in 1924, its etiology and treatments remain, in many instances, problematic. Thrombotic thrombocytopenic purpura remains a rare entity whose etiology is usually unknown, but several drugs and infections have now been implicated in its development (i.e. Cyclosporine A, Mitomycin‐C, Ticlopidine, Simvastatin, Lipitor, Plavix, FK 506, Rapamune (sirolimus), HIV). Although its treatment by plasma exchange has gained worldwide acceptance since the late 1970s, the optimal exchange media is not known, nor the volume and duration of exchange therapy, nor appropriate salvage therapy(ies). Without the benefit of randomized controlled trials, its treatment, to a large extent, remains not evidence‐based but ‘eminence‐based’, making the same mistakes with increasing confidence over an impressive number of years.

Arsine toxicity treated with red blood cell and plasma exchanges

BACKGROUND:  Acute toxicity due to inhalation of arsine gas (AsH3) has no known antidote. Exchange transfusion may be beneficial, and dialysis is often required because arsine may cause acute intravascular hemolysis and renal failure. A patient with arsine toxicity has recently been treated by both red blood cell exchange (RBC‐E) and plasma exchange (PE) therapy and our experience is reported.

Intensive plasma exchange for severe autoimmune hemolytic anemia in a four‐month‐old infant

We report the smallest infant (7.5 kg) to receive intensive plasma exchange (52 PEs) therapy as treatment of autoimmune hemolytic anemia (AIHA). PE temporarily reduces circulating autoantibody levels and can be an effective adjunctive therapy with corticosteroids and cytotoxic drugs or other immuno‐suppressants. Although his clinical course was prolonged and complicated by cytomegalovirus infection with spontaneous perforation of his colon, his recovery was complete. He has remained healthy for more than 2 years.

Ticlopidine-associated ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in 22 persons in Japan: a report from the Southern Network on Adverse Reactions (SONAR)

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder. The classic TTP ‘pentad’ is thrombocytopenia, microangiopathic hemolytic anemia (MAHA), renal impairment, neurological symptoms, and fever (Amorosi & Ultmann, 1966). Laboratory studies identified deficiency of plasma ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motifs 13) activity (ADAMTS13:AC) among some TTP patients (Furlan et al, 1998; Tsai & Lian, 1998). ADAMTS13 cleaves the peptide bond between Thy1605 and Met1606 in the A2 domain of von Willebrand factor (VWF) subunit. VWF is released into the plasma as unusually large VWF multimers (UL-VWFMs), which are degraded into smaller size VWF multimers by ADAMTS13. In the late 1990s, studies in the United States identified 117 cases of TTP that developed after initiation of the thienopyridine, ticlopidine; although at that time, ADAMTS13 activity levels were not widely available (Bennett et al, 1999; Steinhubl et al, 1999). A study of seven patients in the United States with ticlopidine-associated TTP found that all seven had severe deficiency of ADAMTS13 activity and five had detectable antibodies to ADAMTS13 activity (Tsai et al, 2000). We now report on 22 individuals from Japan with ticlopidine-induced TTP and compare these findings to those from the United States. Ticlopidine was the primary anti-platelet agent in Japan from 1989 to 2006. Since 1998, our laboratory at Nara Medical University has been a nationwide referral centre in Japan for thrombotic microangiopathies (TMAs), including TTP (Fujimura & Matsumoto, 2010). The study protocol was approved by the Ethics Committee of Nara Medical University Hospital. TTP diagnostic criteria were: microangiopathic haemolytic anaemia (haemoglobin ≤ 120 g/l), Coombs test negative, undetectable serum haptoglobin (<1 μmol/l), more than 2 fragmented red cells (schistocytes) in a microscopic field with 9100 magnification, increased serum lactate dehydrogenase (LDH) above institutional baseline, thrombocytopenia (platelet count ≤ 100 × 109/l), absence of evidence for disseminated intravascular coagulation and no other identifiable cause of TTP. Additional information on fever ≥37°C; and central nervous system and renal function data were abstracted. Patients were included if, in addition to criteria for idiopathic TTP, the patient had received ticlopidine prior to TTP onset. Before therapeutic plasma exchange or plasma infusion was initiated, whole blood samples (five ml) were withdrawn from each patient and placed into plastic tubes containing 1/10 volume of 3.2% sodium citrate. Plasma was separated by centrifugation at 3000 g for 15 min at 4°C, kept in aliquots at −80°C until testing, and sent to our laboratory with clinical information. Until March 2005, ADAMTS13:AC was determined by classic VWF multimer (VWFM) assay with a detection limit of 3% of the normal control (Furlan et al, 1996; Kinoshita et al, 2001). Thereafter, a chromogenic ADAMTS13-act-enzyme-linked immunosorbent assay (ELISA) with a detection limit of 0-5% of the normal control was developed, and replaced the VWFM assay. Plasma ADAMTS13 inhibitor (ADAMTS13:INH) titres were analysed either by classic VWFM assay or chromogenic ADAMTS13-act-ELISA using heat-inactivated plasmas at 56°C for 30 min. A total of 22 ticlopidine-associated TTP patients fulfilled the inclusion criteria (Table I). Age at diagnosis ranged from 41 to 89 years, with the median age of onset of 69 years. Females accounted for 45.5% of the cohort. Ticlopidine had been administered for a median of 27-5 d (range, 14–35 d) but was discontinued after a clinical diagnosis of TTP was made. Median values for hemoglobin were 83 (60–146) g/l, platelets 9–5 (3.57) × 109/l, and serum creatinine 132.6 (35–380) μmol/l. Abnormal neurological findings were noted in 63.6%. All of the patients had 4 BU/ml. Both ticlopidine-associated TTP deaths did not receive therapeutic plasma exchange. Table I Characteristics of ticlopidine-associated thrombotic thrombocytopenic purpura in Japan and United States. To our knowledge, this is the first study to report detailed characteristics of ticlopidine-associated TTP among patients outside of the United States. Our findings, from a cohort of ticlopidine-associated TTP patients in Japan, identified severe ADAMTS13 deficiency and antibodies to ADAMTS13 in 100% of these 22 individuals. A decade earlier, severe ADAMTS13 deficiency was reported in 100% of seven patients with ticlopidine-associated TTP in the United States and antibodies to ADAMTS13 in five of these patients (Bennett et al, 1999; Tsai et al, 2000). While ticlopidine-induced TTP is undoubtedly a rare disease, it is reassuring that the original observations reported from the United States have been independently replicated in Japan (Bennett et al, 1999; Steinhubl et al, 1999). Limitations of our study should be identified. Follow-up ended at the time of hospital discharge, which prevented us from reporting on relapse rates. Ticlopidine is rarely used today, having been replaced by clopidogrel in 1999 because of safety concerns. Our research has shown that clopidogrel, unlike ticlopidine, does not lead to ADAMTS13 antibody formation and deficiency of ADAMTS13 activity and the rare cases of clopidogrel-associated TTP are not responsive to therapeutic plasma exchange. Also, very little is known about TTP associated with prasugrel (the newest thienopyridine), despite 14 cases of prasugrel-associated TTP having been reported to the Food and Drug Administration in 2009 and 2010 (Jacob et al, 2012). Careful pharmacovigilance to identify severe adverse drug reactions developing among small numbers of persons can serve as important warning signals for potentially serious adverse drug events internationally.

Indications for Emergency Apheresis Procedures

Therapeutic apheresis has gained tremendous popularity worldwide in the last 2 decades. Emergency procedures can be life saving but should be undertaken for limited indications. Our emergency indications and experiences since the 1970s are critically described.

Institutional variation in hemotherapy for solid organ transplantation

Background: Solid organ allograft recipients may require large amounts of blood components. The modification of components to make them safer for iatrogenically immunosuppressed transplant patients increases workload demands on blood banks and transfusion services.

Unexpected hemoglobin electrophoresis results following red cell exchange in a sickle cell anemia patient with acute chest syndrome.

Acute chest syndrome is a well described complication of sickle cell anemia. It is characterized by fever, pulmonary infiltrates, pleuritic chest pain and abnormal pulmonary auscultation. Transfusion therapy, either simple transfusion of red blood cells or a total red blood cell exchange, is a cornerstone therapy for these patients. Exchange transfusion is preferred when an acute reduction of the hemoglobin S (HbS) concentration is the therapeutic goal since it allows one to rapidly reduce the percent HbS without increasing blood viscosity or volume (Wayne, Kevy and Nathan, Blood 1993; 81:1109-1123). Hemoglobin electrophoresis may be used to monitor the effectiveness of the exchange in decreasing HbS. The post-exchange HbS electrophoresis results which were obtained in this case initially caused confusion. In this report we discuss the findings and the reasons why such results may be occasionally expected in future similar situations.