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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.

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. CASE REPORT: A 46-year-old man was accidentally and unknowingly exposed to arsine gas while observing an industrial procedure. Within 6 hours he developed fatigue, nausea, vomiting, and tingling in his extremities and voided dark urine. He quickly developed renal failure secondary to acute arsine toxicity (arsenic level, 1250 µg/L). Laboratory findings were a hematocrit level of 24 percent; blood urea nitrogen and creatinine, 84 and 5.5 mg per dL, respectively; bilirubin, 9.1 mg per dL; indirect bilirubin, 6.8 mg per dL; haptoglobin, less than 6 (normal, 30-200); and lactic dehydrogenase, 10,413 units per L (normal, 265-580). An emergent 1-vol RBC-E transfusion by continuous-flow method revealed dramatic black, grossly hemolyzed plasma. After two additional RBC-E and two PE and daily hemodialysis, he completely recovered over the course of 1 month. CONCLUSION: Patients with arsine toxicity resulting in intravascular hemolysis should receive RBC-E as soon as possible. In addition, PE may be beneficial in removing the components of RBC lysis and further reducing arsenic levels.

An extensive variety of drugs have been associated with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (TTP/HUS). Although a direct causal effect has usually not been proven, the cumulative evidence linking several drugs with TTP/HUS is strong. This paper reviews several categories of drugs including antineoplastics, immunotherapeutics and anti-platelet agents that have been reported to induce TTP/HUS. The pathogenesis of drug-induced TTP/HUS and the effectiveness of treatment regimens are also reviewed. A consensus on diagnostic criteria to accurately and consistently diagnose drug-induced TTP is needed.

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 1990's, 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 (

BACKGROUND: Three types of plasma are widely available for transfusion. Two plasma components, FFP donor retested (FFP-DR), and solvent/detergent-treated plasma (SDP), are now considered to be safer from infectious complications than FFP. STUDY DESIGN AND METHODS: A large regional blood center attempted to provide FFP-DR exclusively to all its 42 hospitals. Significant planning, increases in computer capabilities, and expansion of component storage areas were completed before initiation of this program. RESULTS: During the first 6 months of the FFP-DR program, the blood center was not able to supply the entire region exclusively with FFP-DR. Consequently, SDP was utilized to supplement the program and to successfully and completely convert the region's 42 hospitals to the use of safer plasma. CONCLUSION: Two new plasma components were utilized to completely convert a blood service region to the use of safer plasma.

Dr Herbert Polesky has been a leader in defining the role of transfusion medicine for both medicine and industry. He helped develop the criteria for fundamentals of training programs that physicians would require to become experts in transfusion medicine and paternity testing. He also is one of a small group of pioneers who led the ongoing quest for safer blood products for recipients.

Bone marrow cells expressing the surface antigen CD34 comprise approximately 1% of harvested marrow and are highly enriched for marrow progenitor cells, including the cells believed to be responsible for long-term engraftment following bone marrow transplantation (BMT). Selection of CD34-expressing cells was applied in allogeneic BMT (alloBMT) to decrease the number of T lymphocytes in the infused marrow in an attempt to prevent severe graft-versus-host disease (GVHD). We report 14 patients who underwent HLA-identical sibling-matched alloBMT with marrow-enriched for CD34 cells using the Isolex 300 SA device. Patients received total body irradiation, thiotepa, cyclophosphamide, antithymocyte globulin and methylprednisolone prior to marrow infusion. No post-transplantation immunosuppressive therapy was given except for a 5-week course of steroids. The purity of the infused marrow was 64.9+/-6.0% (mean +/- s.e.m.) CD34-positive cells and patients received a mean of 1.24+/-0.21 x 10(6) CD34 cells/kg. A mean of 9.4+/-1.7 x 10(4) CD3 T cells/kg were present in the CD34-enriched product, representing a 2.7+/-0.1 log depletion. There were no graft rejections and patients achieved a sustained absolute granulocyte count of >500 in a median of 10.5 days and a sustained platelet engraftment of >20000 untransfused in a median of 27 days. Patients were discharged a median of 21.5 days after marrow infusion. There were no instances of grade III or IV graft-versus-host disease (GVHD) and no unexpected adverse events during the transplant hospitalization. With a median follow-up of 12 months, the estimated 100 day survival is 86+/-9%. CD34 selection in alloBMT permits rapid engraftment without unanticipated toxicities.

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.

Chemically modified hemoglobin (Hgb) solutions are being developed for use as blood substitutes. These solutions will cause the serum to appear grossly hemolyzed and will persist in the circulation for up to 4 days. Blood banks may soon need to accept and test patient specimens containing such blood substitutes. To evaluate how routine testing will be affected, we added chemically modified Hgb or 5% albumin to previously tested patient serum specimens with anti-K,-E, -Fya, and -Fyb activity as well as to specimens lacking unexpected red cell antibodies. The diluted specimens were tested using panels of reagent red blood cells. No discrepant results were identified. In addition, red blood cells previously found to be positive and negative by direct antiglobulin test (DAT) were incubated with equal parts of chemically modified Hgb solution or 5% albumin. Repeat DAT testing demonstrated no discrepancies. These studies suggest that the presence of limited amounts of stabilized Hgb will not interfere with routine tests performed in the blood bank.

Nineteen patients, aged 2½ years or younger, underwent liver transplantation at the Indiana University Medical Center. Three required a second graft and one required a third. The transfusion requirements of these children were compared with the needs of adults receiving liver allografts at the same institution. When expressed as units of blood components transfused per kilogram of patient weight, the intraoperative use for the two groups was similar. After surgery, pediatric patients required the greatest hemotherapy support and received considerably larger doses of fresh frozen plasma than did adults. Thus, in contrast to adults, who require greater hemotherapy support during surgery, these pediatric patients required the greatest amount of blood components posttransplantation. Ten of the 19 pediatric patients were cytomegalovirus (CMV)-seronegative before transplantation. Three of the 10 seroconverted after transplantation. Two had received organ grafts from CMV-seropositive donors, but the third received a liver graft and cellular blood components from only CMVseronegative donors. The cause of this patient’s seroconversion was unknown.

Goodpasture's syndrome rarely affects children. Therefore, we present our experience in a young boy whose pulmonary hemorrhage was dramatically resolved by three plasma exchanges. We believe the hemorrhage was caused primarily by acute capillaritis. He received cytoxan and steroids and a series of plasma exchanges which removed/suppressed his anti-glomerular basement membrane (anti-GBM) antibody production. However, after a year, his renal function did not return, and he required renal transplantation and continues to do well.

Although widespread vascular thrombosis is common in thrombotic thrombocytopenic purpura (TTP), there have been no prospective studies on the extent of injury to specific organs. Following successful resuscitation and plasma exchange of an index patient with widespread organ dysfunction, cardiogenic shock, and elevated cardiac troponin-I levels, we prospectively studied and identified 2 more individuals (of 10 consecutive patients) with evidence of myocardial injury/infarction at presentation of acute TTP. These data suggest that cardiac troponin-I measurements should be considered during initial evaluation of all patients with acute TTP.

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. CASE REPORT: Two men (aged 75 and 83 years) developed rapidly fatal TRALI after receiving single units of plasma for correction of elevated international normalized ratios. The donors were found to have white blood cell (WBC) antibodies that included specificities for WBC antigens expressed by the recipient (HLA Class I or Class II and/or HNA-3b [5a] antibody). Autopsy findings in both patients revealed bilateral pleural effusions and extensive patchy areas of alveoli filled with proteinaceous fluid. The pulmonary capillaries were congested with red blood cells and WBCs. Diffuse alveolar damage, including interstitial inflammation, intraalveolar granulocyte infiltration, and hyaline membrane formation, were not identified in either case. CONCLUSION: In both patients the clinical and radiographic findings were indicative of TRALI and indistinguishable from ALI/ARDS. However, diffuse alveolar damage, the classic autopsy finding in ARDS, was not identified, suggesting a different pathogenesis. Further studies are needed on the role of polymorphonuclear cells in the initiating events of TRALI that lead to ALI and the resulting breakdown of the permeability integrity of the alveolar walls.

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. Because of his small size, calcium gluconate was added to replacement fluids and calcium levels closely monitored. The apheresis machine and tubing were routinely primed with red blood cells and FFP substituted for 5% human albumin during the second half of all procedures to maintain adequate levels of procoagulant. Our experience suggests that intensive PE is helpful in controlling severe AIHA and should be considered even for very small patients.

AIDS has created considerable concern among the public regarding being transfused with potentially infectious blood. However, autologous blood donations are still not maximally provided nor utilized. Significant heart disease disqualifies all allogeneic and most autologous blood donors (American Association of Blood Banks (AABB) Standards 1994). Disqualification is based on the widespread belief that donating blood could possibly be detrimental to their health. However, this belief has not been sufficiently documented. Sixty-eight donors (ages 14-84 years), all with histories of significant cardiac diseases, donated 111 units of whole blood (1-3 units). Twenty-eight patients donated 1 unit, 37 donated 2 units, and three patients donated 3 units. Fifty-nine patients had ischemic heart disease, and nine had valvular heart disease (five with mitral stenosis and four with mitral valve prolapse). No patient received erythropoietin, and only one received equal volume replacement with normal saline during donation. All these patients eagerly wished to donate in spite of being informed of the possible complications. No patient wishing to donate has been refused, and none has experienced any adverse consequences from donating. Forty-four patients underwent total hip/knee replacements. Only 56 units (50%) were transfused to 37 patients (54%). Although our experience is limited, it appears that many patients with histories of well established cardiac diseases can easily tolerate donating blood without compromising their health.

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.

Patients with sickle cell disease have abnormal red blood cells (RBCs). This can cause chronic hemolytic anemia and vaso-occlusion leading to tissue hypoxemia and organ dysfunction. RBC exchange transfusion can, without increasing the whole-blood viscosity, quickly replace abnormal erythrocytes with normal and raise the hematocrit resulting in improved delivery of oxygen to hypoxic tissues. Unfortunately, transfusion can also be associated with complications. This paper reviews the role of transfusion, both simple and exchange, in the treatment and prevention of sickle-related complications. The benefits of exchange versus simple transfusion and transfusion versus alternative therapies are discussed.

Priapism is a dramatic, painful complication for some men afflicted by sickle cell anemia. Although the natural history remains unclear, many believe replacing the patient's abnormal red blood cells (RBCs) with normal RBCs by apheresis is effective. However, no controlled trials have demonstrated its effectiveness. We exchanged 7 men after medical management failed. All procedures reduced sickle hemoglobin levels to < 30%. Two patients underwent emergency automated red cell exchanges without any detumescence or reduction of pain. The remaining 5 patients were exchanged non-emergently; 4 experienced no detumescence or relief of pain. One adult experienced resolution 8 h postexchange. However, he had a history of "stuttering" priapism. All required decompression procedures. Automated RBC exchanges were not effective in achieving detumescence or reducing pain.

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 x 10(9)/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.

The Kasabach-Merritt Syndrome describes thrombocytopenia occurring in patients with giant hemangiomata. The resultant thrombocytopenia may be profound and occasionally even life-threatening. An 11-month-old infant with prolonged thrombocytopenia whose course was complicated by recurrent hemorrhaging requiring intense platelet transfusions is reported. During her 19-month hospitalization she received 6,622 platelet concentrates. This represents the most extensive platelet support ever given to an infant with this syndrome.

Background : Many idiopathic thrombotic thrombocytopenia purpura (TTP) patients have severe deficiency of ADAMTS13, an enzyme that cleaves ultralarge von Willebrand multimers. We recently reported that thienopyridine-associated TTP is characterized by an immunologic pathway with severe ADAMTS13 deficiency and a non-immunologic pathway with higher ADAMTS13 activity levels. We now compare findings for idiopathic and thienopyridine-associated TTP patients. Methods : Clinical findings and laboratory findings were evaluated for 51 idiopathic and 39 thienopyridine-associated TTP. Results: Clinical findings were similar between idiopathic and thienopyridine-associated TTP for both severe ADAMTS13 deficient and non-deficient patients. Differences were noted in gender and age, relapse rates, and survival. Conclusion : Among TTP patients with ADAMTS13 deficiency, relapses are frequent in idiopathic TTP patients and Rituximab may be useful, while for thienopyridine-associated TTP patients spontaneous relapse are rare as long as no re-exposure occurs. Among ADAMTS13 non-deficient patients, survival is high following therapeutic plasma exchange (TPE) for idiopathic patients but not for thienopyridine-associated TTP patients. Despite similarities, idiopathic and thienopyridine associated TTP probably have different initiating factors. ADAMTS13 activity and clinical characteristics in idiopathic and thienopyridine-associated TTP Idiopathic severe ADAMTS13 deficiency (n=29) †Thienopyridine severe ADAMTS13 deficiency (n=26) Idiopathic non-severe ADAMTS13 deficiency (n=22) †Thienopyridine non-severe ADAMTS13 deficiency (n=13) *p2.5 mg/dl* 11% 27% 48% 46% 30-day survival 96% 85% 90% 62% Long-term relapse* 42% 8% 0% 0% Neutralizing autoantibodies to ADAMTS13 (prior to TPE) § 79% 100% 27% 0% Neutralizing autoantibodies to ADAMTS 13 (measured at remission) § 55% 33%‡ 33% 0%

Although much has been learned about the pathophysiologic process of thrombotic thrombocytopenic purpura (TTP), both diagnostically and therapeutically, since its initial description by Moschowitz 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. Although treatment by plasma exchange has gained worldwide acceptance, the optimal exchange media is not known, nor the volume and duration of exchange therapy, not appropriate salvage therapies. 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 decades.