Characterization of clopidogrel hypersensitivity reactions and management with oral steroids without clopidogrel discontinuation.

OBJECTIVES: The purpose of this study was to characterize clopidogrel hypersensitivity and describe its successful management with oral steroids without clopidogrel discontinuation. BACKGROUND: Hypersensitivity reactions to clopidogrel are poorly understood and present difficulty in management. METHODS: Patients diagnosed with clopidogrel hypersensitivity after percutaneous coronary intervention underwent evaluation and received oral prednisone without clopidogrel discontinuation. Cutaneous testing was performed after completion of clopidogrel therapy for diagnosis and assessment of cross-reactivity. RESULTS: Sixty-two patients representing 1.6% of the percutaneous coronary intervention population developed clopidogrel hypersensitivity during the study period. The mean age was 62 ± 11 years, 71% of patients were male, and 35% reported prior adverse drug reaction. Clopidogrel hypersensitivity manifested as generalized exanthema in 79%, localized skin reaction in 16%, and angioedema or urticaria in 5% of patients. Biopsy of affected areas demonstrated a lymphocyte-mediated delayed hypersensitivity reaction. Complete resolution of hypersensitivity reaction was observed in 61 patients (98%) with a short course of oral prednisone. Cutaneous testing confirmed delayed hypersensitivity reaction to clopidogrel in 34 (81%) and immediate hypersensitivity in 3 of 42 patients (7%) tested. Allergenic cross-reactivity was observed for ticlopidine in 10 (24%), prasugrel in 7 (17%), and both ticlopidine and prasugrel in 3 patients (7%). Histological examination showed lymphocyte-mediated hypersensitivity in abnormal patch test areas. CONCLUSIONS: Clopidogrel hypersensitivity is manifested as generalized exanthema and is caused by a lymphocyte-mediated delayed hypersensitivity in most patients. This can be managed with oral steroids without clopidogrel discontinuation. Allergenic cross-reactivity with ticlopidine, prasugrel, or both is present in a significant number of patients with clopidogrel hypersensitivity.

Recent progress in understanding the pathogenesis of immune thrombocytopenia.

PURPOSE OF REVIEW: Immune thrombocytopenia (ITP) is a bleeding disorder in which both antibody and cell-mediated autoimmune responses are directed against an individual's own platelets and/or megakaryocytes, leading to either enhanced platelet destruction and/or reduced platelet production, respectively. The cause of this platelet-specific autoimmunity remains unknown, but there has been a constant stream of recent publications that suggest ITP is the result of T-cell dysregulation. RECENT FINDINGS: In the last 18 months, a rich tapestry of studies has emerged that seems to clarify some immunopathologic issues in ITP while raising new questions related to ITP pathogenesis. The current view on the immunopathogenic mechanisms associated with ITP appears to particularly concentrate on how incompetent CD4+ T-regulatory cells (Tregs) allow autoimmune effector mechanisms to proceed and cause thrombocytopenia. There is a parallel body of recent literature focusing on molecular mimicry mechanisms, B-cell abnormalities, abnormal cytokine patterns and genetic studies in ITP. Of interest, one can recognize inter-relationships between these immune dysregulations. SUMMARY: This article will discuss the literature from the past 18 months pertaining to these observations and will show that whereas many of the T-cell defects have been clarified, new questions have also come to light and more immunopathological research is warranted.

A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell-mediated responses that are differentially sensitive to therapy.

Immune thrombocytopenia (ITP) is a bleeding disorder characterized by antibody-opsonized platelets being prematurely destroyed in the spleen, although some patients with ITP may have a cell-mediated form of thrombocytopenia. Although several animal models of ITP have been developed, few mimic primary chronic ITP nor have any shown cell-mediated platelet destruction. To create this type of model, splenocytes from CD61 knockout mice immunized against CD61(+) platelets were transferred into severe combined immunodeficient (SCID) (CD61(+)) mouse recipients, and their platelet counts and phenotypes were observed. As few as 5 x 10(4) splenocytes induced a significant thrombocytopenia and bleeding mortality (80%) in recipients within 3 weeks after transfer. Depletion of lymphocyte subsets before transfer showed that the splenocyte's ability to induce thrombocytopenia and bleeding completely depended on CD4(+) T helper cells and that both CD19(+) B cell (antibody)- and CD8(+) T cell (cell)-mediated effector mechanisms were responsible. Treatment of the SCID mouse recipients with intravenous gamma-globulins raised platelet counts and completely prevented bleeding mortality induced by antibody-mediated effector mechanisms but did not affect cell-mediated disease. This novel model not only shows both antibody- and cell-mediated ITP and bleeding but also suggests that these 2 effector mechanisms have a differential response to therapy.

Gamma testing experience with the ACL TOP hemostasis testing system.

As a gamma testing site or a limited early release site for the ACL TOP, St. Michael's Hematology Laboratory evaluated the ACL TOP for its ability to fit into a laboratory whose workflow includes large volumes of routine and specialty hemostasis assays. This evaluation included the determination of the ACL TOP's precision, normal ranges, and reagent sensitivities. Analytical correlation studies for the ACL TOP were performed in comparison to the ACL ADVANCE. The ACL TOP was also tested for its ability to handle large volumes of not only routine assays but also more specialized coagulation assays. Instrument precision, normal reference range assignment, and factor sensitivities met the requirements of this laboratory. The ACL TOP correlated favorably to the ACL ADVANCE, and in a workup for thrombophilia its throughput was twice what was seen with the ACL ADVANCE. The speed of the ACL TOP was impressive, generating results at a rate of almost 5 results/min. In this gamma testing study, the ACL TOP has demonstrated suitability as a precise coagulation analyzer for use in the settings of a high-volume, fast-paced, specialized coagulation laboratory faced with demanding turnaround times.

A patient with anemia of obscure origin: Crohn's disease in disguise.

BACKGROUND: A 65-year-old white Mediterranean male with a 10-year history of intermittent anemia, who was otherwise completely asymptomatic, was referred to our hospital in March 2004. He had a medical history of beta thalassemia and fecal occult blood tests had occasionally been positive. INVESTIGATIONS: Fecal occult blood test, laboratory investigations, esophagogastroduodenoscopy, colonoscopy with retrograde ileoscopy, mesenteric angiography, small-bowel series, CT scan of the abdomen and pelvis, Meckel's scan, and capsule endoscopy. Laparoscopic surgery followed by macroscopic and microscopic histopathologic examination of samples obtained during the procedure. DIAGNOSIS: Crohn's disease of the small bowel. MANAGEMENT: Laparoscopic segmental small-bowel resection with end-to-end anastomosis. Postsurgical treatment with Pentasa 4 g a day.

Immunoadsorption of factor VIII inhibitors.

PURPOSE OF REVIEW: Extracorporeal immunoadsorption is being increasingly applied in a variety of disorders. This approach is particularly suited to removal of antibodies or inhibitors to coagulation factor VIII and may be particularly useful before the administration of large amounts of expensive replacement or bypass therapy for patients with hemophilia who are bleeding, or patients undergoing immune tolerance therapy. RECENT FINDINGS: In patients with inhibitors to factor VIII, several types of immunoadsorption therapy have been used, although reports are mainly anecdotal, consisting of relatively small numbers of persons. Nonetheless, the findings suggest that immunoadsorption may be clinically effective and cost-effective and should be considered early in the treatment of appropriate patients. New immunoadsorption technologies are being described for a variety of disorders, including hemophilia, and a new synthetic matrix of polystyrene beads functionalized with sulfonate and tyrosyl methylester groups for immunoadsorption removal of factor VIII inhibitors is intriguing. SUMMARY: Although immunoadsorption was shown to be clinically effective in patients with inhibitors to factor VIII more than two decades ago, recent papers have emphasized the desirability of early implementation of the modality in the treatment plan. Immunoadsorption is relatively easy to perform with few adverse effects, but specialized equipment is required, and it should be performed in an experienced setting. Although potentially less costly than other (bypass) therapies, immunoadsorption is itself not inexpensive, and its comparative effectiveness with plasmapheresis and other management options for the dangerously bleeding patient with antibodies to factor VIII should be determined by multicenter randomized controlled trials. Interesting recent novel technical developments in the field may facilitate increased use of the procedure.

Immunoadsorption may provide a cost-effective approach to management of patients with inhibitors to FVIII.

BACKGROUND: Immunoadsorption of plasma with Staphylococcal protein A removes immunoglobulins and immune complexes; hence, it should effectively remove inhibitors to FVIII in acquired or congenital hemophilia. The procedure may be cost effective, given the expense of therapies used to treat patients with inhibitors, particularly in an acute setting. STUDY DESIGN AND METHODS: Three patients with inhibitors to FVIII were treated with the Excorim Immunosorba system (two columns used in tandem). Costs for immunoadsorption and for other therapeutic products administered to the patients were calculated. RESULTS: Two patients had acquired hemophilia and severe bleeding associated with low levels of circulating FVIII and high levels of inhibitors to FVIII. They failed to achieve a satisfactory response to management with immunosuppression, pFVIII, recombinant FVIIa or IVIG but responded rapidly, with long-term benefit, to immunoadsorption therapy. The third patient had congenital hemophilia and immunoadsorption was effective in reducing his inhibitor level, allowing him to undergo immune tolerance therapy. Costs of treatment before immunoadsorption were markedly higher than those associated with the immunoadsorption procedures (i.e., >Can 350,000 dollars and >Can 1,000,000 dollars vs. < 20,000 dollars). CONCLUSION: Immunoadsorption appears to be an effective and cost-effective alternative in the management of patients with inhibitors to FVIII.

Thrombotic thrombocytopenic purpura associated with a prolactin-producing pituitary adenoma.

We report here the case of a 44-year-old woman with thrombocytopenia, anemia, convulsions, hyperprolactinemia, and galactorrhea. The patient died of cardiac failure. Autopsy revealed PAS-positive and von Willebrand factor-positive microthrombi in the arterioles and capillaries of many organs, mainly in the heart and brain, confirming the clinical diagnosis of thrombotic thrombocytopenic purpura. In the pituitary, a prolactin-producing adenoma was identified. To our knowledge, thrombotic thrombocytopenic purpura accompanied by a prolactin-secreting pituitary adenoma has not yet been described. The question of whether the association between the vascular changes and the pituitary adenoma is incidental or causal cannot be answered. Further studies are required to determine whether prolactin released from the pituitary tumor in excess played a role in the formation of microthrombi causing multiple organ failure and the demise of the patient.

Cellular immune mechanisms in autoimmune thrombocytopenic purpura: An update.

Autoimmune thrombocytopenic purpura (AITP) is a bleeding disorder in which autoantibodies are directed against an individual's own platelets, leading to enhanced clearance through Fc receptor (R)-mediated phagocytosis by macrophages residing in the reticuloendothelial system (RES), particularly in the spleen. The production of IgG autoantibodies is critically dependent on cellular immune mechanisms particularly relating to T cells. We review the recent literature of the cell-mediated immunology of AITP focusing on platelet phenotype, genetics, T-cell reactivities, and cytokine profiles in patients with AITP. Understanding the interaction between these cell-mediated mechanisms is vital for developing antigen specific immunotherapies to treat this autoimmune disease.