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. 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.

Arsine toxicity treated with red blood cell and plasma exchanges.

BACKGROUND: Acute toxicity due to inhalation of arsine gas (AsH(3)) 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 microg/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.

Thrombotic thrombocytopenic purpura: yesterday, today, tomorrow.

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.

Drug-induced thrombotic thrombocytopenic purpura/hemolytic uremic syndrome: a concise review.

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.

What are appropriate initial and salvage therapies for patients with thrombotic thrombocyopenic purpura (TTP)?

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.

Myocardial infarction/injury is relatively common at presentation of acute thrombotic thrombocytopenic purpura: the Indiana University experience.

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.

The role of red blood cell exchange transfusion in the treatment and prevention of complications of sickle cell disease.

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.