Leo J. McCarthy

Thrombotic Thrombocytopenic Purpura Associated with Clopidogrel

BACKGROUND The antiplatelet drug clopidogrel is a new thienopyridine derivative whose mechanism of action and chemical structure are similar to those of ticlopidine. The estimated incidence of ticlopidine-associated thrombotic thrombocytopenic purpura is 1 per 1600 to 5000 patients treated, whereas no clopidogrel-associated cases were observed among 20,000 closely monitored patients treated in phase 3 clinical trials and cohort studies. Because of the association between ticlopidine use and thrombotic thrombocytopenic purpura and other adverse effects, clopidogrel has largely replaced ticlopidine in clinical practice. More than 3 million patients have received clopidogrel. We report the clinical and laboratory findings in 11 patients in whom thrombotic thrombocytopenic purpura developed during or soon after treatment with clopidogrel. METHODS The 11 patients were identified by active surveillance by the medical directors of blood banks (3 patients), hematologists (6), and the manufacturer of clopidogrel (2). RESULTS Ten of the 11 patients received clopidogrel for 14 days or less before the onset of thrombotic thrombocytopenic purpura. Although 10 of the 11 patients had a response to plasma exchange, 2 required 20 or more exchanges before clinical improvement occurred, and 2 had relapses while not receiving clopidogrel. One patient died despite undergoing plasma exchange soon after diagnosis. CONCLUSIONS Thrombotic thrombocytopenic purpura can occur after the initiation of clopidogrel therapy, often within the first two weeks of treatment. Physicians should be aware of the possibility of this syndrome when initiating clopidogrel treatment.

Hyperleukocytic Leukemias and Leukostasis: A Review of Pathophysiology, Clinical Presentation and Management

Acute hyperleukocytic leukemias (AHL) are associated with a very high early mortality rate mostly due to respiratory failure or intracranial bleeding. The pathophysiological process leading to these complications is called leukostasis but the biological mechanisms underlying its development and progression remain unclear. Although traditionally related to “overcrowding” of leukemic blasts in the capillaries of the microcirculation, leukostasis is likely to result from direct endothelial cell damage. This damage is probably mediated by soluble cytokines released during the interaction between leukemic cells and vascular endothelium and by the subsequent migration of leukemic blasts in the perivascular space. Leukemic cells ability to respond to chemotactic cytokines and their expression of specific adhesion molecules are probably more important in determining whether leukostasis will develop than the number of circulating blasts. This could explain why leukostasis does not develop in all patients with AHL. The identification of the adhesion molecules, cytokines and receptors mediating endothelial cell damage in AHL should become a priority if therapeutic improvements are desired. Leukapheresis is widely used but it is unclear whether it provides additional benefit to a simpler and less invasive intervention with allopurinol, hydroxyurea and intravenous fluids. Cranial irradiation is not generally recommended. Induction chemotherapy should be started without delay. It is hoped that specific pharmacological inhibitors of the interaction between leukemic cells and vascular endothelum will result in an improved outcome for this very high-risk population.

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.

Glycogen‐rich clear cell carcinoma of the breast: A light and electron microscopic study

A glycogen‐rich clear cell carcinoma arose in the breast of a 49‐year‐old woman. Light microscopic examination of the neoplasm revealed both intraductal papillary growth and stromal invasion. Electron microscopic examination demonstrated neoplastic cells that contained massive quantities of nonmembrane‐bound particulate glycogen and that formed numerous acini. Apically, these cells formed microvilli; laterally they formed tight junctions and desmosomes. Morphologic features of this neoplasm are similar to those of the fetal breast and to some other clear cell carcinomas arising elsewhere in the body.

Semiautomated processing of bone marrow grafts for transplantation

This report describes experience with a technique for the isolation of mononuclear cells from large quantities of human bone marrow using a blood cell processor. The procedure includes the separation of the bone marrow aspirates by concentrating and collecting interface buffy coat cells. A mononuclear white cell‐enriched fraction is then obtained with ficoll‐hypaque in the blood cell processor. Finally, the bone marrow white cells are washed to remove the ficoll‐hypaque and the contaminating plasma. The entire procedure is carried out in a closed system. The automated method of isolating mononuclear cells proved superior to the manual method in both the recovery of cells and the time needed to process the marrow. Also, the risk of microbial contamination is substantially reduced. When marrow white cells processed by this method and cryopreserved were transfused subsequently into patients who had previously undergone high‐dose chemotherapy and radiotherapy, engraftment, as indicated by a rise in the absolute granulocyte count of >1000 per mm3, occurred within 20 days. This semiautomated technique provides a convenient, rapid, and reliable method for processing and preparing large numbers of viable marrow cells.

Use of sentinel sites for daily monitoring of the US blood supply

BACKGROUND : This report describes the first year of a government‐sponsored program that uses daily reports from 29 sentinel sites to monitor the capacity of the US blood supply to meet demand.

The use of exchange transfusions: a potentially useful adjunct in the treatment of fulminant falciparum malaria.

Fulminant falciparum malaria with greater than 500,000/mm3 parasites in the peripheral blood portends a poor prognosis. We recently managed a patient who had greater than 1.2 million/mm3 parasitized erythrocytes in her peripheral blood, following initially inadequate antimalarial therapy, with exchange transfusion in addition to conventional chemotherapy. This patient recovered from her disease despite severe cerebral involvement and acute failure. We feel that exchange transfusion was a useful adjunct and should be considered in patients with life threatening falciparum malaria when conventional measures fail to control the disease.

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.

Fatal transfusion‐transmitted Babesia microti in the Midwest

Fatal transfusion-transmitted Babesia microti is rare. Because it is not uniformly reported, its incidence can only be estimated at less than 1:1,000,000 per red blood cell (RBC)-containing product. Transfusion transmission usually occurs in northeastern United States with more than 50 cases now reported. The disease is usually asymptomatic; however, in asplenic, elderly, or immunosuppressed individuals, it may be fatal. This fatal case is unique because it was contracted in Indiana from an Indiana donor. A 61-year-old woman with end-stage renal disease and congestive heart failure received 4 RBC units for lower gastrointestinal bleeding. Subsequently, she complained of nausea and fever to 39.4°C. Approximately 15 percent of her RBCs contained trophozoites, which were reduced to 1 to 2 percent by RBC exchange. Her treatment included intravenous quinidine and clindamycin and then converted to quinine. Unfortunately, disseminated intravascular coagulation and septic shock developed, and she expired within 1 week. No autopsy was performed. One of the transfused units showed evidence of B. microti infestation by immunofluorescence antibody, immunoglobulin M 1:20, and immunoglobulin G of more than 1:256. Her only risk factor was transfusion, and B. microti was confirmed by the Centers for Disease Control and Prevention morphologically, serologically, and by polymerase chain reaction. The implicated asymptomatic donor recalled exposure to wooded areas but not a tick bite and was permanently deferred.The photomicrograph illustrates polyparasitism with tetrad or Maltese cross formation and polymorphism, all characteristic of Babesia infection.

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.