In vivo efficacy of shipped HLA-matched platelets

BACKGROUND: Platelet (PLT) concentrates are currently stored in an incubator at 20 to 24 degrees C with continuous gentle agitation. PLTs are routinely shipped for transfusion to thrombocytopenic patients, however. There is a concern that PLT concentrates may be adversely affected during the shipping process. CASE REPORT: A 40-year-old woman with severe aplastic anemia and immune refractory to unselected PLT transfusions was transferred to a distant medical center for a hematopoietic peripheral blood progenitor cell transplant where she continued to receive HLA-matched PLTs from her dedicated donors. Sixteen such components were collected and air-shipped in insulated boxes to the transplant center. Thirty-seven plateletpheresis components from the same dedicated donors had been transfused to the patient before transfer. Corrected count increments (CCIs) at the two sites were compared, with assessment of the role of HLA-match grades. The mean interruption time of controlled agitation during shipment was approximately 10.5 hours. The mean CCI of all distant transfusions was 14,450 +/- 9700 PLTs per microL x m2 per 10(11) and that of local transfusions was 10730 +/- 4870. The mean donor-paired difference between CCIs at the two sites was 1140 +/- 9940. At the remote location no clinically significant bleeding occurred and one posttransfusion febrile reaction was noted. CONCLUSION: Despite the study limitations, the effectiveness, in a single patient, of leukoreduced, irradiated apheresis PLTs shipped by lengthy combined surface and airline transport is reported, as measured by posttransfusion CCIs.     

Potential for transfusion-associated graft-versus-host disease due to apheresis platelets matched for HLA class I antigens

Transfusion-associated graft-versus-host disease (TA-GVHD) has been reported in immunocompetent recipients of nonirradiated cellular blood components from donors who are homozygous for an HLA haplotype shared with the patient. In these cases, donor lymphocytes have no antigens foreign to the recipient, and this similarity in HLA antigens appears important for the development of TA-GVHD. Experience with 65 patients receiving apheresis platelets matched for class I HLA antigens was reviewed to determine the incidence of such a transfusion among HLA- matched, unrelated donor-recipient pairs. In 5 percent of transfusions (31/673), the patient received lymphocytes from a donor exhibiting no antigens foreign to the recipient, but the patient had additional HLA-A or -B antigens not present on donor lymphocytes. Twenty-three percent (n = 15) of patients received at least one such transfusion. In addition, most patients were immunosuppressed as a result of their underlying disease or therapy, which may decrease the degree of antigen matching required to initiate TA-GVHD. Until the pathogenesis of this disease is better understood, it is recommended that the transfusion of an HLA-matched cellular blood component be considered a risk factor for the development of TA-GVHD regardless of the patient's immune status, and that all such blood components be irradiated.     

Endometrial ablation as an alternative to hysterectomy

In the United States, as many as two million women (ie, 22%) each year will consult a physician about menorrhagia (ie, excessive menstrual bleeding). Seven hundred thousand hysterectomies are performed in the United States each year for symptomatic menorrhagia. The procedure cost, risk, and complications, combined with the fact that a large number of posthysterectomy specimens show no abnormality, suggest that the majority of hysterectomies performed for menorrhagia are unnecessary. These data suggest that a less invasive procedure that destroys the endometrial lining but preserves the uterus would be a beneficial procedure for patients with excessive uterine bleeding. Treatment for menorrhagia may include hormone therapy, endometrial curettage, endometrial ablation, and hysterectomy. Women who are opposed to hysterectomy and those for whom other treatment options were unsuccessful can consider ablation rather than hysterectomy.     

Anticalins as an alternative to antibody technology

Anticalins are a class of engineered ligand-binding proteins that are based on the lipocalin scaffold. The lipocalin protein architecture is characterised by a compact, rigid beta-barrel that supports four structurally hypervariable loops. These loops form a pocket for the specific complexation of differing target molecules. Natural lipocalins occur in human plasma and body fluids, where they usually function in the transport of vitamins, steroids or metabolic compounds. Using targeted mutagenesis of the loop region and biochemical selection techniques, variants with novel ligand specificities, both for low-molecular weight substances and for macromolecular protein targets, can be generated. Due to their small size, typically between 160 and 180 residues, robust tertiary structure and composition of a single polypeptide chain, such 'anticalins' provide several advantages over antibodies concerning economy of production, stability during storage, faster pharmacokinetics and better tissue penetration. At present, anticalins offer three major mechanisms for therapeutic application: (i) as antidotes, by quickly removing toxic or otherwise irritating compounds from the human body; (ii) as antagonists, for example, by binding to cellular receptors and blocking them from interaction with their natural signalling molecules; (iii) as tissue-targeting vehicles, by addressing toxic molecules or enzymes to disease-related cell surface proteins.     

Anticalins as an alternative to antibody technology

Anticalins are a class of engineered ligand-binding proteins that are based on the lipocalin scaffold. The lipocalin protein architecture is characterised by a compact, rigid β-barrel that supports four structurally hypervariable loops. These loops form a pocket for the specific complexation of differing target molecules. Natural lipocalins occur in human plasma and body fluids, where they usually function in the transport of vitamins, steroids or metabolic compounds. Using targeted mutagenesis of the loop region and biochemical selection techniques, variants with novel ligand specificities, both for low-molecular weight substances and for macromolecular protein targets, can be generated. Due to their small size, typically between 160 and 180 residues, robust tertiary structure and composition of a single polypeptide chain, such ‘anticalins’ provide several advantages over antibodies concerning economy of production, stability during storage, faster pharmacokinetics and better tissue penetration. At present, anticalins offer three major mechanisms for therapeutic application: (i) as antidotes, by quickly removing toxic or otherwise irritating compounds from the human body; (ii) as antagonists, for example, by binding to cellular receptors and blocking them from interaction with their natural signalling molecules; (iii) as tissue-targeting vehicles, by addressing toxic molecules or enzymes to disease-related cell surface proteins.     

The Johnson-Neyman procedure as an alternative to ANCOVA

ANCOVA is a widely used statistical procedure that is particularly useful in analyzing data from experimental designs. There are, however, a number of assumptions that must be tested before proceeding with the ANCOVA. Of particular concern is the assumption of homogeneity of regression slopes (HOS). When the HOS assumption has been violated, the researcher needs to look for an alternative approach to the ANCOVA. The Johnson-Neyman procedure (J-N) is presented as such an alternative. Although the calculations for the procedure are somewhat tedious and are not currently a standard feature of statistical software packages, an alternative approach using SAS syntax codes is presented.     

Stimulation of hematopoiesis as an alternative to transfusion

Optimal parenteral nutritional support, provided concomitantly with extraordinarily large replacement doses of intravenous iron dextran can be safe, effective, and life-saving for severely anemic patients who cannot or will not accept erythrocyte transfusion. Five patients who had sustained massive acute blood loss and two who had severe chronic anemia received as much as 140 ml of iron dextran intravenously. The average initial hemoglobin value in the patients with acute blood loss was 4.7 gm/dl (range 2.6 to 8.4 gm/dl), increasing to an average of 9.8 gm/dl (range 7.5 to 12.8) in 23.4 days (range 17 to 30 days), a 166% increase. The average initial hemoglobin value in the patients with chronic anemia was 3.7 gm/dl, increasing to 10.5 gm/dl over an average period of 121 days, a 182% increase. Total abdominal colectomy, pyloroplasty with truncal vagotomy, and highly selective vagotomy were accomplished without complications in four of the patients. There were no adverse reactions to the therapeutic regimen, and all patients were discharged in good condition.     

Cytotoxic T cell recognition of an endogenous class I HLA peptide presented by a class II HLA molecule

Human leukocytes were stimulated in vitro with peptides corresponding in sequence to the highly variable helix of the alpha 1 domain of various HLA-B and -C molecules. A CD4+ CD8- cytotoxic T cell line, CTL-AV, that is specific for the HLA-B7 peptide presented by HLA-DR11.1 was obtained. The HLA-DR11.2 molecule, which only differs at three residues from HLA-DR11.1, did not present the HLA-B7 peptide to CTL-AV. Peptides from the alpha 1 domain helix of other HLA-A and HLA-B molecules, but not HLA-C molecules, competed with the HLA-B7 peptide for binding to HLA-DR11.1. A cell line (WT50) that coexpresses HLA-B7 and HLA-DR11.1 was killed by CTL-AV in the absence of any added HLA-B7 peptide. The processing and presentation of HLA-B7 in these cells appears to be through the endogenous, and not the exogenous, pathway of antigen presentation. Thus, Brefeldin A inhibits presentation and chloroquine does not. Furthermore, introduction of purified HLA-B7 molecules into HLA-DR11.1+, HLA-B7- cells by cytoplasmic loading via osmotic lysis of pinosomes, but not by simple incubation, rendered them susceptible to CTL-AV killing. These results provide an example of class II major histocompatibility complex (MHC) presentation of a constitutively synthesized self protein that uses the endogenous pathway of antigen presentation. They also emphasize the capacity for presentation of MHC peptides by MHC molecules.     

Bivalirudin,a bivalent,thrombin specific anticoagulant as an alternative to heparin in interventional procedures as an alternative to heparin in interventional procedures

Among the antithrombotic therapies evaluated to date, the synthetic peptide bivalirudin is unique in its ability to reduce both ischemic and bleeding complications associated with percutaneous coronary intervention (PCI). Bivalirudin is a small peptide consisting of 20 amino acid residues that binds thrombin in a direct, reversible, and bivalent fashion. The agent is approved for use in the United States and New Zealand as an anticoagulant in patients with unstable angina undergoing PCI and may also prove beneficial in patients with acute coronary syndromes (ACS), acute myocardial infarction (AMI) and in patients undergoing coronary artery bypass graft (CABG) procedures. This article examines bivalirudin in more detail.     

Docetaxel as an alternative to paclitaxel after acute hypersensitivity reactions

OBJECTIVE: To review the mechanism involved in paclitaxel-induced hypersensitivity reactions and to evaluate the potential use of docetaxel after acute hypersensitivity reactions (HSRs) to paclitaxel. DATA SOURCES: Literature identified through a MEDLINE search (1966-September 2000) and through secondary sources. DATA SYNTHESIS: HSRs to paclitaxel can be life-threatening. The exact etiology involved in paclitaxel-induced HSRs has not been fully elucidated; the reactions may be due to the Cremophor EL vehicle or to paclitaxel itself. Options for treatment following HSRs are limited. A rechallenge attempt can be made, but is not always successful. Docetaxel, a semisynthetic taxane, may have a role in therapy for patients unable to tolerate paclitaxel therapy. This review examines the etiology of paclitaxel-induced HSRs and the potential role of docetaxel following these acute reactions. CONCLUSIONS: Docetaxel may be a viable alternative for patients who experience HSRs to paclitaxel.