Platelet refractoriness and alloimmunization in pediatric oncology and bone marrow transplant patients

BACKGROUND: The purposes of this study were to determine the overall incidence of platelet refractoriness and alloimmunization among multiply transfused children on a medical oncology and bone marrow transplant service and to evaluate the effect of routine white cell reduction in blood components on that incidence. STUDY DESIGN AND METHODS : The platelet transfusion records of 128 consecutive children admitted to the hospital and requiring blood component support for the treatment of disease were evaluated retrospectively. Mean corrected count increments (CCIs) for each patient were calculated for all random- donor platelet transfusions given within 7 days of the routine weekly testings of the patient's serum for lymphocytotoxic antibodies (LCTAbs). Mean CCIs for HLA-matched platelet transfusions were calculated separately for the patients receiving them. RESULTS : Thirty- one patients (24%) had or developed persistently positive LCTAbs (patient's serum reacted with > or = 3/10 panel lymphocytes); 22 (71%) of these patients had a mean CCI < 7.5 to random-donor platelet transfusions. In contrast, of the 97 patients with negative or transiently positive LCTAbs, only 25 (26%) had a mean CCI < 7.5. The overall incidence of platelet refractoriness (CCI < 7.5) was 37 percent. Patients with acute myelogenous leukemia had a significantly (p < 0.01) reduced incidence (17%) of low CCIs, with or without positive LCTAbs, as compared to patients with other malignant or nonmalignant disorders (41%). No difference in the incidence of LCTAbs or low CCIs was seen in patients undergoing allogeneic or autologous bone marrow transplant or receiving drug therapy only. Among the 24 patients who received HLA-matched platelets, only those with positive LCTAbs showed a significant improvement in CCIs over that achieved with random-donor platelet transfusions. Routine white cell reduction in red cell and platelet components with third-generation white cell filters was performed prior to transfusion in 73 of the patients. There was no significant difference between the incidence of LCTAbs and/or low CCIs in this group and that in the 55 children receiving unfiltered transfusions. CONCLUSION : Alloimmunization and platelet refractoriness occur in pediatric oncology and bone marrow transplant patients, but the incidence-particularly in children with acute myelogenous leukemia- -appears to be low. The detection of LCTAbs predicts a poor response to random-donor platelet transfusion, but most such patients show improved CCIs with HLA-matched platelets. Routine use of white cell-reduction filters has thus far failed to eliminate alloimmunization in children requiring prolonged blood component support.     

Health-related quality of life after elective surgery

Objective:  To examine the responsiveness of the 36-Item Short Form Health Survey (SF-36) to clinical changes in three surgical groups and to study how health-related quality of life (HRQL) changes with time among patients who undergo total hip arthroplasty, thoracic surgery for treatment of non-small-cell lung cancer, or abdominal aortic aneurysm (AAA) repair. Design:  Prospective cohort study with serial evaluations of HRQL preoperatively and at 1, 6, and 12 months after surgery. Setting:  University tertiary care hospital. Patients:  Of 528 patients, more than 50 years of age, who were admitted for these elective procedures, 454 (86%) provided preoperative health status data and are members of the study cohort. At 12 months after surgery, 439 (93%) of the cohort was successfully contacted and 390 (90%) provided follow-up interviews. Measurements and main results:  The Medical Outcomes Study SF-36, the Specific Activity Scale, five validated health transition questions, and a 0 to 100 scale measure of global health were used to assess changes in health status at 1, 6, and 12 months after surgery. Change in health status as measured by the SF-36 demonstrated that physical function and role limitations due to physical health problems were worse 1 month after these three surgeries. However, by 6 months after surgery, most patients experienced significant gains in the majority of the dimensions of health, and these gains were sustained at 12 months after surgery. Longitudinal changes in the SF-36 were positively associated with responses to the five health transition questions, to changes on the Specific Activity Scale and global health rating question, and to clinical parameters for persons who had AAA repair. These findings indicate that the SF-36 has evidence of validity and is responsive to expected changes in HRQL after elective surgery for these procedures. Conclusions:  For the total hip arthroplasty patients, responsiveness was greatest for the SF-36 scales that measure physical constructs. However, for the two other procedures and at various points of recovery, significant changes were observed for all eight subscales, suggesting that responsiveness was dependent on the type of surgery and the timing of follow-up, and that multidimensional measures are needed to fully capture changes in HRQL after surgery. Funded in part by a grant from the Agency for Health Care Policy and Research (1RO1-HS06573). Dr. Mangione is the recipient of a Clinical Investigator Award (1K08-AG00605) from the National Institute on Aging, and is an awardee of the Robert Wood Johnson Foundation Generalist Physicians Faculty Scholars Program (029250).     

Monoclonal Antibody Recognizing a Unique Rh-Related Specificity

A mouse IgG1 monoclonal antibody (MAb) UMRh, was prepared by immunizing Balb/c mice with the Jurkat T cell acute lymphoblastic leukemia (T-ALL) cell line. The MAb UMRh is directed against a widely distributed Rh-related cell surface antigen, present on red blood cells (RBCs) expressing the more common Rh phenotypes. The antigen has reduced expression on RBCs of-D-, DC^W-/DC^W-, Rh_mod and Rh_null phenotypes. UMRh immunoblotted a unique pattern on RBC membrane preparations of two bands at 40 and 43 kD and a diffuse pattern extending upward to about 55 kD. The UMRh antigen is also present on peripheral blood mononuclear cells, granulocytes, platelets. leukemic cells of T cell, B cell and myeloid origins, hematopoietic stem cells, and two tumor lines (lung and colon carcinoma). The number of UMRh sites per RBC (CDe/ce) was determined to be 5,519 copies/cell, whereas the sites on a -D- phenotype RBC were 1,096 copies/cell. A T-ALL line (CEM) expressed 333,364 copies/cell and a myeloid line (KG-1) expressed 90,913 copies/cell. Several Rh-related murine MAbs have been described, but our data indicates that UMRh recognizes a previously uncharacterized Rh-related specificity.     

Human herpesvirus 6: infection and disease following autologous and allogeneic bone marrow transplantation

Human herpesvirus 6 activity (HHV-6) was studied in 15 allogeneic and 11 autologous marrow transplantation patients. After transplantation, HHV-6 was isolated from the peripheral blood mononuclear cells of 12 of 26 patients (6 allogeneic and 6 autologous). All isolates were variant B. Eleven of 26 and 12 of 19 patients showed salivary shedding of HHV-6 DNA before and after transplantation, respectively. The antibody titer increased in 7 of 26 patients. Thus, 23 of 26 patients showed evidence of active HHV-6 infection either by virus isolation, salivary shedding, or increases in antibody titers. The fraction of saliva specimens positive in 19 patients was negatively associated with their antibody titers (P= .005). The proportion of cultures positive increased after transplantation (P = .007). Sinusitis was associated with HHV-6 isolation in autologous recipients (P= .002). In allogeneic patients, active human cytomegalovirus infection was associated with HHV-6 isolation (P = .04). No association was observed between HHV-6 infection and GVHD, pneumonia, delay in engraftment, or marrow suppression. Of the 120 clinical events analyzed in 26 patients, HHV-6 was defined as a probable cause of 16 events in 9 patients based on the propinquity of HHV-6 activity and the clinical event plus the absence of other identified causes of the event.     

Plateletpheresis in the management of thrombocytosis

Acute thrombotic and hemorrhagic manifestations of thrombocytosis associated with myeloproliferative disorders may be life threatening. Conventional therapy with radioisotopes and/or cytotoxic drugs may require weeks for effective control of platelet counts. In five patients, plateletpheresis by discontinuous-flow (Haemonetics) or continuous-flow (Aminco Celltrifuge) centrifugation was used as a means of reducing platelet counts acutely. With each procedure, approximately 2-9 X 10(12) platelets were removed, resulting in decrements in platelet counts and relief of symptoms. Plateletpheresis is a useful and safe acute means of controlling platelet counts in myeloproliferative disorders.     

Profound differences in virus population genetics correspond to protection from CD4 decline resulting from feline lentivirus coinfection

CD4 decline is a hallmark of disease onset in individuals infected with Feline Immunodeficiency Virus (FIV) or Human Immunodeficiency Virus type 1 (HIV-1). Cats that are infected with a poorly replicating, apathogenic FIV (PLV) prior to exposure to a virulent FIV strain (FIVC) maintain CD4 numbers by mechanisms that are not correlated with a measurable adaptive immune response or reduction in circulating viral load. We employed population genetic approaches based on the 3' portion of the viral genome to estimate the population structure of FIVC from single and dual infected cats. In dual infected cats, FIVC effective population size was decreased during the initial viral expansion phase, and after three weeks of infection, the population declined sharply. The FIVC population recovered to pre-bottleneck levels approximately seven weeks post-FIVC infection. However, the population emerging from the bottleneck in dual infected cats was distinct based on estimates of temporal population structure and substitution profiles. The transition to transversion rate ratio (κ) increased from early to late phases in dual infected cats due primarily to a decrease in transversions whereas in single infected cats, κ declined over time. Although one clone with extensive G to A substitutions, indicative of host cytidine deaminase editing, was recovered from a dual infected cat during the bottleneck, the post bottleneck population had an overall reduction in G to A substitutions. These data are consistent with a model of PLV-induced host restriction, putatively involving host DNA editing, that alters the dynamics of FIVC throughout the course of infection leading to disease attenuation.     

Translational profiling of cardiomyocytes identifies an early Jak1/Stat3 injury response required for zebrafish heart regeneration

Certain lower vertebrates like zebrafish activate proliferation of spared cardiomyocytes after cardiac injury to regenerate lost heart muscle. Here, we used translating ribosome affinity purification to profile translating RNAs in zebrafish cardiomyocytes during heart regeneration. We identified dynamic induction of several Jak1/Stat3 pathway members following trauma, events accompanied by cytokine production. Transgenic Stat3 inhibition in cardiomyocytes restricted injury-induced proliferation and regeneration, but did not reduce cardiogenesis during animal growth. The secreted protein Rln3a was induced in a Stat3-dependent manner by injury, and exogenous Rln3 delivery during Stat3 inhibition stimulated cardiomyocyte proliferation. Our results identify an injury-specific cardiomyocyte program essential for heart regeneration.