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Biomedical subjects

S J Slichter

Publications and source records attributed to S J Slichter.

At least 19 recordsLinked to original sources
PubMed1991

Molecular cloning and in vivo evaluation of canine granulocyte-macrophage colony-stimulating factor.

Canine granulocyte-macrophage colony-stimulating factor (caGM-CSF) was cloned and expressed to allow further investigation of GM-CSF in a large animal model. The cDNA is 850 base pairs (bp) long and encodes a peptide of 144 amino acids. The nucleotide and amino acid sequence homology between caGM-CSF and human GM-CSF (hGM-CSF) is 80% and 70%, respectively. A mammalian expression vector pCMV/CAGM was constructed and used to transfect COS cells for expression of caGM-CSF. Supernatant from transfected COS cells enriched with caGM-CSF was shown to have significant stimulating activity in granulocyte-macrophage colony forming unit (CFU-GM) assays of canine marrow. caGM-CSF, expressed from bacteria, was used to treat seven dogs at varying doses twice daily subcutaneously (sc) for 14 to 16 days. Circulating blood neutrophils and monocytes increased significantly. The increase in circulating eosinophils was variable. Thrombocytopenia developed during administration of caGM-CSF but corrected rapidly after cessation of treatment. Evaluation of survival times of 51Cr-labeled autologous platelets suggested increased consumption as the primary reason for thrombocytopenia. A species-specific GM-CSF will be a useful tool for hematologic or immunologic studies in dogs.

Amino Acid Sequence↗
PubMed1991

Use of leukocyte-depleted platelets and cytomegalovirus-seronegative red blood cells for prevention of primary cytomegalovirus infection after marrow transplant.

Seventy-seven cytomegalovirus (CMV)-seronegative marrow transplant patients were randomized in a prospective controlled trial comparing the use of leukocyte-depleted platelets plus CMV-seronegative red blood cells with standard unscreened blood products for the prevention of primary CMV infection during the first 100 days after transplant. Eligible patients included CMV-seronegative patients undergoing autologous transplant or seronegative patients undergoing allogeneic transplant for aplastic anemia or non-hematologic malignancy who had seronegative marrow donors. Patients and marrow donors were serologically screened for CMV and randomized before conditioning for transplant and followed for CMV infection with weekly cultures of throat, urine, and blood and with weekly CMV serologies until day 100 after transplant. Leukocyte-depleted platelets were prepared by centrifugation, a procedure that removed greater than 99% of leukocytes. There were no CMV infections observed in 35 evaluable treatment patients compared with seven infections in 30 evaluable control patients (P = .0013). There was no statistically significant difference in the mean number of platelet concentrates in the treatment patients (164 concentrates) compared with the control patients (126 concentrates). Leukocyte-depleted platelets plus CMV-seronegative red blood cells are highly effective in preventing primary CMV infection after marrow transplant.

Adolescent↗
PubMed1991

Identification of alloimmunized patients: use of radiolabeled allogeneic platelet kinetic measurements and platelet antibody tests.

In a group of stable, nonthrombocytopenic leukemia patients awaiting bone marrow transplantation, results of paired allogeneic radiolabeled platelet kinetic measurements were correlated with the results of several different platelet and lymphocytotoxic antibody tests to determine which parameters could be used to identify patients who were alloimmunized to platelets. Seven patients with acute leukemia who had been transfused during induction therapy were used as the test group, and, as a control group, five untransfused patients with chronic myelogenous leukemia were also studied. Concurrent fibrinogen survival measurements were performed in all patients to assess whether hemostatic factor consumption (ie, disseminated intravascular coagulation) was present. Allogeneic platelet survival measurements were reduced from normal in all 12 study patients. In 8 of 12 patients, fibrinogen and platelet survival measurements were comparably reduced, suggesting disease-related platelet consumption. In four heavily transfused patients with acute leukemia, allogeneic platelet survivals were markedly reduced to less than or equal to 2.1 days, compared with the 3.5- to 7.4-day platelet survival measurements found in the other eight patients. The disproportionately short platelet survivals compared with fibrinogen survival measurements in these four patients, combined with documented positive antibody tests to their donors' platelets in the three patients with evaluable tests, suggested that these patients had become alloimmunized to platelets because of their prior transfusions. There was substantial concordance between the two radiolabeled allogeneic donor platelet survival measurements performed in each of these patients, suggesting that host rather than donor factors have a major influence on transfusion outcome (r = .93, P less than .001). The platelet cross-match tests, using the radiolabeled protein Staph A assay combined with the IgG enzyme-linked immunosorbent assay test, had the best correlation with the posttransfusion recovery and survival of the donors' platelets.

ABO Blood-Group System↗
PubMed1990

Inhibition of the enzyme purine nucleoside phosphorylase (PNP) reduces refractoriness to transfused platelets in a dog model.

To better define the role of T-cells in alloimmunization, we induced purine nucleoside phosphorylase (PNP) deficiency in a dog platelet transfusion model. Short-term administration of eight different drug schedules using several combinations of the PNP inhibitor 8-aminoguanosine and/or deoxyguanosine did not induce significant toxicity in four treated animals as demonstrated by blood chemistries, cell counts, and autologous platelet recovery and survival measurements. However, continuous long-term daily administration of these agents produced significant renal and/or hepatic toxicity leading to death in five of six animals. Modification of the drug schedule to early short-term administration of both deoxyguanosine and 8-aminoguanosine, followed by long-term intermittent doses of only 8-aminoguanosine, was not only well tolerated by all the animals but also resulted in significant immunosuppression. Overall, six of nine evaluable dogs (67%) treated with some combination of PNP inhibitors did not become refractory to eight weekly transfusions of platelets from a single random donor dog, P less than 0.005, compared to untreated controls, only 3/21 (14%) not immunized. Furthermore, in four evaluable recipients, discontinuation of the 8-aminoguanosine while continuing platelet transfusions from their original donors did not result in refractoriness. In addition, these four recipients were also unable to recognize platelets from two other random donors. This suggests that both specific and non-specific tolerance to foreign platelet antigens had been induced by PNP-inhibitor therapy. Other evidence for the efficacy of this immunosuppressive treatment was the almost normal post-transfusion recovery and survival of donor platelets, both during and after treatment. This suggests failure to form even low levels of platelet alloantibodies in the immunosuppressed recipients. In contrast, B-cell immunity to soluble antigens was intact as demonstrated by a normal antibody response to keyhole limpet haemocyanin (KLH) antigen.

Animals↗
PubMed1990

Platelet transfusion therapy.

This article reviews appropriate platelet support of those patients who are chronically thrombocytopenic because of decreased platelet production, including those receiving chemotherapy or radiation treatments and those undergoing bone marrow transplants. The platelet products available for transfusion and the indications for platelet transfusions are discussed. Expected responses to platelet transfusions are reviewed as well as the prevention of platelet alloimmunization. Finally, a discussion of the mechanisms and management of platelet refractoriness is included.

Adult↗
PubMed1990

A pilot study of continuous infusion heparin for the prevention of hepatic veno-occlusive disease after bone marrow transplantation.

Twenty-eight patients undergoing marrow transplantation participated in a pilot study to determine the safety of continuous infusion heparin for the prevention of veno-occlusive disease (VOD) of the liver. Four doses of continuous infusion heparin were administered, ranging from a dose prolonging the partial thromboplastin time (PTT) to 1.5-2.0 times the patients' baseline value, to a dose prolonging the PTT to less than 1.2 times the patients' baseline value. Seven patients (25%) received a full course of heparin, beginning from the day the preparative therapy started through day 14 post-transplant (range 20-26 days on heparin). In 21 patients infusions were ended before day 14 post-transplant, a median of 16 days on heparin (range 1-26 days). Of these, 14 patients were withdrawn from heparin because of bleeding and seven were withdrawn because of anticipated bleeding. Bleeding was observed in 27 patients and was minor in 25. Two patients developed major bleeding in the gastrointestinal tract which was not fatal. Minor bleeding was observed in 27 of 28 case control patients who did not receive heparin. The sites of bleeding were similar in control and heparin treated patients. VOD developed in 20 patients (71%) and was sever or fatal in four (14%). The prevalence of VOD was not influenced by the dosage of heparin or the duration of its administration. We conclude that low dose heparin resulting in marginal prolongation of the PTT may be infused into patients undergoing marrow transplantation with a low risk of serious bleeding. Further studies are needed to evaluate its efficacy.

Adult↗
PubMed1989

Mechanisms of response to treatment in autoimmune thrombocytopenic purpura.

To determine the mechanisms of an increase in the platelet count after therapy for autoimmune thrombocytopenic purpura, we determined the survival time and localization of radiolabeled autologous platelets and measured platelet-associated immunoglobulin levels before and after prednisone therapy or splenectomy in 19 patients with the disease. Eleven of 12 patients (92 percent) responded to prednisone with a mean threefold increase in the platelet count, resulting from increased platelet production (P less than 0.005); platelet survival was unchanged. Treatment with steroids failed in only one patient, whose pretreatment platelet production was already above normal. After splenectomy, 6 of 10 patients had a mean fourfold rise in the platelet count that correlated with increased platelet survival (P less than 0.005), together with improved platelet recovery (the percentage of platelets circulating in the blood immediately after the injection). Platelet production was unchanged. Base-line 111In-labeled platelet localization in the liver was normal in five patients in whom splenectomy was effective and increased to above normal in two of three in whom it was ineffective. Total platelet localization in the liver and spleen decreased by more than half after successful splenectomy (P less than 0.001), whereas it decreased by less than 25 percent after unsuccessful splenectomy. Platelet-associated immunoglobulin levels neither predicted nor correlated with treatment responses to prednisone or splenectomy. We conclude that prednisone improves platelet counts primarily by increasing platelet production, whereas the effect of splenectomy is to prolong platelet survival. Baseline measurements of platelet turnover and of platelet localization in the liver may be helpful in predicting the response to prednisone or splenectomy, respectively.

Adolescent↗
PubMed1989

A model to determine required pool size for HLA-typed community donor apheresis programs.

Community donor plateletpheresis programs must have adequate numbers of HLA-typed donors to support the transfusion needs of alloimmunized patients, and donor pool size calculations should reflect the fact that each patient needs more than one donor to provide his or her support. The average number of donors needed to provide a patient's support was estimated as a function of donor usage and commitment. A model was developed for determining an appropriate size of the donor pool for a community donor plateletpheresis program that would incorporate the average number of donors needed per patient, the level of HLA compatibility to be maintained between patient and donor, and the frequencies of patient and donor HLA phenotypes. A database of 4338 plateletpheresis transfusions given to 591 patients from a pool of up to 870 community donors over a 3-year period was analyzed retrospectively to validate the estimates of the average number of donors needed to support a patient, which ranged from 4 to 33 donors. This database was also used to illustrate the application of the pool size determination model. Model results suggest that plateletpheresis donor pools of 1000 to 3000 donors are capable of meeting the transfusion needs of most patients at an HLA-match grade of B2 or better.

Blood Component Removal↗
PubMed1989

Factors influencing the transfusion response to HLA-selected apheresis donor platelets in patients refractory to random platelet concentrates.

Immune and nonimmune causes of platelet refractoriness were evaluated in a group of patients receiving HLA-selected single-donor platelet transfusions. During a 1-year observation period, 1 h and 24 h platelet recoveries wre determined after 522 single-donor platelet transfusions given to 43 patients persistently refractory to pooled random-donor platelet transfusions. 72% of patients tested ultimately developed lymphocytotoxic antibodies suggesting they were alloimmunized. When significant lymphocytotoxic antibodies were demonstrable in these patients, HLA well-matched platelet transfusions consistently produced good transfusion responses. In contrast, patients without lymphocytotoxic antibodies had clinical factors that adversely affected transfusion outcome (P less than 0.0001). Fever and splenomegaly markedly reduced 1 h post-transfusion platelet recoveries, while sepsis compromised the 24 h platelet recovery. Overall, the presence of any clinical factor was most likely to reduce 1 h platelet recovery, while donor-recipient HLA incompatibilities correlated best with poor 24 h post-transfusion platelet recovery. A platelet crossmatch test predicted the transfusion response when non-immune clinical factors were absent.

Antilymphocyte Serum↗
PubMed1989

Platelet destruction in autoimmune thrombocytopenic purpura: kinetics and clearance of indium-111-labeled autologous platelets.

Using autologous 111In-labeled platelets, platelet kinetics and the sites of platelet destruction were assessed in 16 normal subjects (13 with and three without spleens), in 17 studies of patients with primary autoimmune thrombocytopenic purpura (AITP), in six studies of patients with secondary AITP, in ten studies of patients with AITP following splenectomy, and in five thrombocytopenic patients with myelodysplastic syndromes. In normal subjects, the spleen accounted for 24 +/- 4% of platelet destruction and the liver for 15 +/- 2%. Untreated patients with primary AITP had increased splenic destruction (40 +/- 14%, p less than 0.001) but not hepatic destruction (13 +/- 5%). Compared with untreated patients, prednisone treated patients did not have significantly different spleen and liver platelet sequestration. Patients with secondary AITP had similar platelet counts, platelet survivals, and increases in splenic destruction of platelets as did patients with primary AITP. In contrast, patients with myelodysplastic syndromes had a normal pattern of platelet destruction. In AITP patients following splenectomy, the five nonresponders all had a marked increase (greater than 45%) in liver destruction compared to five responders (all less than 40%). Among all patients with primary or secondary AITP, there was an inverse relationship between the percent of platelets destroyed in the liver plus spleen and both the platelet count (r = 0.75, p less than 0.001) and the platelet survival (r = 0.86, p less than 0.001). In a stepwise multiple linear regression analysis, total liver plus spleen platelet destruction, the platelet survival and the platelet turnover were all significant independent predictors of the platelet count. Thus platelet destruction is shifted to the spleen in primary and secondary AITP. Failure of splenectomy is associated with a marked elevation in liver destruction. The magnitude of spleen and liver destruction appears to be of considerable importance in the severity of the disease, as reflected in the platelet survival and platelet count.

Autoimmune Diseases↗
PubMed1989

Engraftment and transfusion requirements after allogeneic marrow transplantation for patients with acute non-lymphocytic leukemia in first complete remission.

This retrospective study analysed factors affecting engraftment and transfusion requirements of platelets and red blood cells in 303 patients transplanted for acute non-lymphocytic leukemia in first remission from HLA-identical or one-antigen mismatched donors. Multivariant analysis showed that the most important factors affecting the speed of engraftment were drugs used for graft-versus-host disease (GVHD) prophylaxis, the development of acute GVHD and HLA matching. Factors affecting only granulocyte recovery included patient age and sex. The radiation regimen used for preparing patients affected the time to platelet independence. Patients transplanted in laminar airflow rooms took longer to achieve red cell independence and required more units of red cells and platelets than patients transplanted in regular rooms. In addition, ABO incompatibility affected red cell transfusion requirements while GVHD prophylaxis and acute GVHD influenced both red blood cells and platelet support.

Adult↗
PubMed1989

Graft-v-host disease is associated with autoimmune-like thrombocytopenia.

Persistent thrombocytopenia after allogeneic marrow transplantation is associated with poor patient survival. To identify the mechanisms of the thrombocytopenia, we studied platelet and fibrinogen kinetics and antiplatelet antibodies in 20 patients between 60 and 649 days (median 90) after transplantation. Seventeen patients had isolated thrombocytopenia (less than 100 X 10(9) platelets/L): the marrow cellularity was normal in five patients and slightly reduced in 12, and there was no discrepancy between thrombopoiesis and myeloerythropoiesis. Three patients had pancytopenia following marrow graft rejection (two) and relapse of leukemia (one). Only three patients had evidence of increased platelet production, indicating that in most cases there is a poor marrow response to thrombocytopenia early after marrow grafting. There was no correlation between platelet count and splenic pooling, suggesting that hypersplenism was an unlikely mechanism of the thrombocytopenia. Although there was a direct relationship between platelet count and platelet survival, the reduction in platelet survival was greater than what could be explained by the fixed platelet removal found in thrombocytopenic patients; this suggests increased platelet destruction. Seven patients had intercurrent infections that reduced both platelet and fibrinogen survivals. In addition, platelet antibodies bound to autologous or marrow donor platelets were present in five of the 12 patients studied. Patients with antiplatelet antibodies had lower platelet counts (30 +/- 10 X 10(9)/L v. 49.1 +/- 28.7 X 10(9)/L, P less than 0.05) and platelet survivals (1.32 +/- 0.92 days v. 3.58 +/- 2.02 days, P less than 0.05) than patients without antiplatelet antibodies. Furthermore, platelet-bound autoantibodies were present in five of six patients with grade II-IV acute or chronic graft-versus-host disease (GVHD), but were not present in six patients free of GVHD (P less than 0.01). We conclude that persistent thrombocytopenia after marrow transplantation is most often secondary to increased platelet destruction mediated by multiple mechanisms and that platelet autoantibodies are found in patients with acute or chronic GVHD.

Adolescent↗
PubMed1988

Transfusion and bone marrow transplantation.

Bone marrow transplantation has prolonged the lives of a significant percentage of patients with a variety of both malignant and nonmalignant disorders. However, the impact of this treatment on a transfusion service is substantial. Large numbers of often specialized blood products are required to support these patients, and the logistics of accomplishing this taxes the ingenuity and resources of even large regional blood programs.

Blood Transfusion↗
PubMed1987

Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance.

Mechanisms of thrombocytopenia were studied in 38 patients with mild to moderately severe chronic autoimmune thrombocytopenia (AITP). 51Cr and 111In-labeled autologous platelet turnover studies and in vitro analysis of committed megakaryocyte progenitors (CFU-Meg) were used as independent measures of platelet production. Autologous 111In-labeled platelet localization studies were performed to assess platelet clearance. Although there was no increase in the frequency of marrow CFU-Meg, a specific increase in the CFU-Meg [3H]TdR suicide rate was seen which was inversely correlated with the platelet count (P less than 0.001). Platelet turnover studies showed significant numbers of patients had inappropriate thrombopoietic responses to their reduced platelet counts. Platelet-associated antibody levels correlated inversely with platelet turnover suggesting that antiplatelet antibody impairs platelet production. The circulating platelet count was best predicted by an index relating platelet production (i.e., turnover) to the spleen-liver platelet clearance that correlated directly with platelet survival (P less than 0.001). In summary, both depressed platelet production and increased platelet clearance by the liver and spleen contribute to the thrombocytopenia of AITP.

Autoantibodies↗
PubMed1987

Refractoriness to random donor platelet transfusions in patients with aplastic anaemia: a multivariate analysis of data from 264 cases.

Frequent platelet support is an essential part of the management of patients with severe aplastic anaemia and platelet transfusions from random donors are usually given as initial therapy. To evaluate those parameters that might correlate with the development of refractoriness to platelets from random donors, we performed a retrospective multivariate analysis in 264 patients with severe aplastic anaemia who presented for allogeneic bone marrow transplantation. Two hundred and ten (79.5%) of these patients had received multiple platelet and red cell transfusions, and 71 (34%) were refractory to random donor platelets. The strongest factor correlating with refractoriness was the presence of lymphocytotoxic antibodies, followed by the number of platelet units previously transfused. However, the latter variable attained significance only when the number of platelet units transfused exceeded 40. When given HLA-compatible platelet transfusions, only five (7%) of the refractory patients did not show a reasonable post-transfusion platelet increment. Measures which would delay or prevent platelet alloimmunization might include a policy of therapeutic rather than prophylactic platelet transfusions, and referring patients early in the course of their disease for marrow grafting if a suitable donor is available.

Adolescent↗
PubMed1987

Prevention of platelet alloimmunization in dogs with systemic cyclosporine and by UV-irradiation or cyclosporine-loading of donor platelets.

To study the immunosuppressive effects of three different treatments, 30 dogs received at weekly intervals eight platelet transfusions from a single random donor dog. The three experimental protocols were daily oral cyclosporine (Cs) treatment of recipients; in vitro ultraviolet (UV)-irradiation of donor platelets; and Cs-loading of donor platelets. All nine recipients of Cs, 11/12 (92%) recipients of UV-irradiated platelets, and 5/9 (56%) recipients of Cs-loaded donor platelets remained nonimmunized to repeated transfusions of donor platelets. In contrast, only 3 of 21 untreated controls (14%) were not alloimmunized by donor platelets. Moreover, 44% to 67% of the nonimmunized recipients remained tolerant to continued platelet transfusions from their original donor even after experimental therapy was discontinued. Forty-three percent to 100% of transfusions from secondary donors were also accepted without causing alloimmunization, suggesting that tolerance induced by prior treatment was not specific for the primary donor. However, survival of both the original and secondary donor platelets was reduced to about half the starting level, suggesting that some immune response to platelets had occurred. Also, recipients immunized by their original donor's platelets frequently developed refractoriness to platelets from other donors.

Animals↗
PubMed1986

The effects of splenectomy on engraftment and platelet transfusion requirements in patients with chronic myelogenous leukemia undergoing marrow transplantation.

Granulocyte and platelet recovery as well as platelet transfusion requirements following allogeneic marrow transplantation were analyzed in 67 patients with chronic myelogenous leukemia in the chronic phase. Twenty patients had splenectomy prior to transplantation. Forty-seven patients were transplanted without splenectomy, 21 of whom had splenic enlargement by physical examination. There were no differences in the proportion of patients with granulocyte recovery, but the recovery of peripheral granulocytes to levels of 200, 500 and 1,000/mm3 occurred more rapidly in the splenectomy group than in the no-splenectomy group. Patients with splenectomy received platelet transfusions for a mean of 10 (2-36) days as compared to 20 (3-82) days for patients without splenectomy (p less than .001). Eighteen (90%) patients with splenectomy became platelet transfusion independent at a median of 16 (2-32) days after transplantation as compared to 40 (85%) patients without splenectomy who became transfusion independent at a median of 28 (15-86) days (p less than .001). The proportion of patients achieving platelet levels of 50 and 100 X 10(3)/mm3 did not differ between the two groups (p = .07), but patients in the splenectomy group achieved these levels more rapidly following transplant (p less than .001). One of 17 evaluable patients in the splenectomy group and 31 of 46 in the no-splenectomy group became refractory to random platelets (p less than .001) and required platelets from family members or unrelated completely or partially HLA matched donors. In the no-splenectomy group, splenic size did not affect the speed of granulocyte or platelet recovery or platelet transfusion requirements.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗