Transfusion-associated graft-versus-host disease, monoclonal gammopathy and PCR.
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Acute Disease↗
Biomedical subjects
D H Pamphilon
Publications and source records attributed to D H Pamphilon.
Acquired factor XI inhibitor in chronic lymphocytic leukaemia.
A 71 year old man with chronic lymphocytic leukaemia (CLL) experienced excessive bleeding following transurethral resection of the prostate. Investigations showed a prolonged kaolin cephalin clotting time (KCCT) with low concentrations of factor XI. The prolonged KCCT was largely corrected by mixing with normal plasma but this correction was lost on incubation, confirming the presence of an inhibitor. He was treated with pulsed methylprednisolone and chlorambucil which resulted in the resolution of the bleeding problem and the loss of detectable circulating inhibitor.
Aged↗
The alloimmunized patient: effective transfusion support and newer experimental approaches.
Refractoriness occurs in a proportion of patients who receive multiple platelet transfusions. Alloantibodies, in particular those directed against the class I human leucocyte antigens (HLA) present on the platelet surface, are frequently associated with accelerated platelet destruction and transfusion failure. Compatible platelets for transfusion may be found by selecting donations from HLA-typed individuals, crossmatching patients' sera against donor lymphocytes and platelets or both. Maintaining a large panel of HLA-typed apheresis donors is expensive and some mismatching is inevitable due to the polymorphic nature of the HLA system. Cross-matching may improve the outcome when HLA-matched donations are transfused and may also be a cost-effective strategy for the selection of compatible untyped platelets. Administration of intravenous immunoglobulin, plasma exchange and ex vivo removal of platelet HLA have been employed successfully in a few refractory alloimmunized patients but do not yet have an established role. Experimental studies in animal models suggest that it may be possible to induce tolerance to HLA and prevent alloimmunization.
Animals↗
Ultraviolet-B irradiation of platelet concentrates: a strategy to reduce transfusion recipient allosensitization.
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Antigens↗
Studies of allogeneic bone marrow and spleen cell transplantation in a murine model using ultraviolet-B light.
Ultraviolet irradiation inhibits alloreactive and mitogen-induced responses and might reduce both graft-versus-host and host-versus-graft reactions after bone marrow transplantation (BMT). We have studied proliferative responses to mitogens and reactivity in mixed lymphocyte culture after irradiation with ultraviolet (UV)-B light using splenocytes from Balb/c (H-2d) and CBA (H-2k) mice. Response to mitogens and in MLC was strongly inhibited by 20 J/m2 and abolished at 50 J/m2. Clonogenic cell recovery (CFU-GM; CFU-S) after UV-B irradiation was also reduced. When bone marrow and spleen cells were transplanted from parent (Balb/c) animals into F1 hybrid (Balb/c X CBA) recipients, all animals died with features indicative of graft-versus-host disease (GVHD) in 34 days. If the grafts were first irradiated with 100 J/m2 of UV-B at a mean wavelength of 310 nm, then 76% survived to day 80 when they were killed and shown to have normal marrow cellularity. The remainder died in marrow aplasia or of GVHD. H-2 typing in a group of surviving recipients showed either donor hematopoiesis only (8 of 15), mixed allogeneic chimerism (5 of 15), or recipient type hematopoiesis (2 of 15). Higher doses (200 to 300 J/m2) were detrimental to survival with 88% of recipients dying in marrow aplasia. Syngeneic BMT in Balb/c mice showed slower hematopoietic reconstitution when the grafts were first irradiated with 100 J/m2. After BMT from Balb/c to CBA mice all recipients of unirradiated grafts died within 54 days. By contrast, after graft irradiation with 100 J/m2 survival of recipient animals to day 80 was 59%. If these grafts were treated with 50 J/m2 survival was only 26% with an increase in deaths due to GVHD. Hematopoiesis at day 80 in a group of survivors studied by Ig heavy chain allotyping indicated donor type hematopoiesis in 6 of 10 (50 J/m2) and 2 of 9 (100 J/m2). These data indicate that UV-B irradiation inhibits lymphocyte reactivity and can prevent GVHD. However, there is clear in vitro and in vivo evidence of stem cell damage, such that autologous marrow recovery was demonstrated in a proportion of recipients. In parent----F1 UV-irradiated transplants, sustained hematopoietic recovery was effected in the majority by donor stem cells.
Animals↗
Immunomodulation by ultraviolet light: clinical studies and biological effects.
The interest of immunologists in ultraviolet (UV) irradiation stems from observations made in vitro and in vivo. In vitro, UV irradiation inhibits mitogen and mixed lymphocyte culture (MLC) responses and in vivo, it can induce cutaneous anergy, apparently via suppressor cells and serum factors. At present much interest is focused on the possible use of UV irradiation to permit transfusion without allosensitization and transplantation without either rejection or graft-versus-host disease (GVHD). Here, Derwood Pamphilon and colleagues discuss the current uses and potential of UV irradiation in transfusion and transplantation and relate these to experimental evidence on its effects at the cellular level.
Animals↗
Platelet transfusions irradiated with ultraviolet-B light may have a role in reducing recipient alloimmunization.
The recipients of multiple platelet transfusions frequently develop alloantibodies directed against the human leucocyte antigens (HLA) present on both leucocytes and platelets. Such alloimmunization (AI) may result in refractoriness to further platelet transfusions. Contaminating leucocytes bearing Class II HLA and present in platelet concentrates (PC) are responsible for the formation of HLA antibodies and their removal by filtration reduces the rate of recipient AI. Ultraviolet irradiation (UVR) of PC at an appropriate dose inactivates the contaminating mononuclear leucocytes so that responses in vitro to mitogens and alloantigens are abrogated. It seems likely that UV-irradiation of donor dendritic cells (DC) is important in preventing in vitro responses to alloantigens and in vivo allosensitization. At the same time, satisfactory platelet function and structure is retained when measured by in vitro tests. In vivo assessments of platelet recovery and survival in healthy subjects and the ability to correct the bleeding time in thrombocytopenic patients are comparable to non-irradiated PC. Prospective studies are now in progress to determine if UVR will reduce recipient AI to HLA in multiply-transfused patients with leukaemia and lymphoma.
Antigens, Surface↗
Comparison of platelet-rich plasma collection using the Haemonetics PCS and Baxter Autopheresis C.
We have compared 118 platelet-rich plasma donations collected using the Autopheresis-C Platelet cell (Auto C) with 166 donations using the Haemonetics PCS. The median platelet yield from the Auto C was superior (2.51 vs. 1.54 x 10(11] although collection times differed (60 vs./40 min). There was greater variability in the platelet yield from the Auto C (0.45-5.6 vs./0.26-2.8 x 10(11], but leucocyte contamination was not significantly different. After secondary processing, there was significantly less residual platelet-poor plasma (272 vs. 369 ml). Platelet function assessed during 5 days of storage was satisfactory for both, although platelet aggregation responses to collagen and adenosine diphosphate were superior in the Auto C platelets.
Humans↗
Comparability of haematological and biochemical parameters before and after apheresis of volunteer donors.
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Alkaline Phosphatase↗
Graft-versus-host disease in children receiving HLA-identical allogeneic bone marrow transplants with a low adjusted T lymphocyte dose.
Fourteen children with high risk leukaemia received allogeneic bone marrow transplants from HLA-identical MLC-compatible sibling donors. All bone marrows were T cell depleted and a T cell addback was prepared from the donor's peripheral blood so that the mean total number of CD3+ cells given was 2.6 (1.0-4.1) x 10(5)/kg recipient body weight. This was administered as a short infusion prior to the bone marrow. The children were conditioned with 1440 cGy fractionated total body irradiation and cyclophosphamide 120 mg/kg and were not given cyclosporin A or methotrexate. All patients engrafted and none showed late graft rejection. Acute graft-versus-host disease (GVHD) developed in nine of 14 children and required treatment with steroids. Two children with grade IV GVHD and one with grade I acute GVHD who subsequently developed severe chronic GVHD died. There have been two relapses (both fatal) and one death from cytomegalovirus pneumonitis. Survival is currently 57% (8/14) with a mean follow-up of 548 days (range 384-810). A high incidence of GVHD which was fatal in three patients can occur despite infusion of low T cell numbers in the absence of post-graft immunosuppression.
Adolescent↗
Bone marrow processing on the Haemonetics V50 cell separator.
We have processed 27 bone marrow (BM) harvests using the Haemonetics V50 cell separator with a paediatric plasmapheresis set and programmed for lymphocyte collection. The mean starting volume of 843 mL was processed in 6-8 cycles to a buffy coat (BC) with a mean volume of 230 mL. The mean starting mononuclear cell (MNC) count was 1.22 x 10 8/kg recipient weight, and recovery was 92%. Clonogenic potential of the BC was assessed using CFU-GM assays and recovery was measured after cryopreservation or purging. On 4 occasions where major ABO incompatibility existed between donor and recipient, both BM and BC were consecutively diluted in compatible blood and processed twice. This achieved a calculated reduction in donor erythrocytes of 98%. The procedure was efficient and yielded a BC fraction suitable for cryopreservation and purging. Adequate stem-cells were retained as verified by CFU-GM assays and documentation of stable engraftment.
Adolescent↗
Platelet concentrates irradiated with ultraviolet light retain satisfactory in vitro storage characteristics and in vivo survival.
We have previously reported that platelet concentrates (PC) may be irradiated with ultraviolet light (UVL) in a cryostorage pack such that mixed lymphocyte reactions (MLR) are abolished whilst satisfactory platelet function is retained during subsequent storage using Fenwal PL-1240 containers. We have now studied both platelet structure and function after irradiation in DuPont Stericell bags which are both UV-permeable and biocompatible. The irradiation dosage was 3000 Joules/m2 of UVL at a mean wavelength of 310 nm; a dose previously shown to abolish MLR. No detriment to platelet function was observed when compared to control as measured by aggregation responses to adenosine diphosphate (ADP), collagen and ristocetin, hypotonic shock response and pH during 5 d of storage. Lactate levels were significantly higher (P less than 0.01) and glucose levels lower (P less than 0.01) in UV-treated PC, although in the majority the lactate level did not exceed 20 mmol/l. Betathromboglobulin and platelet factor 4 levels were higher during storage in the UV group, the latter reaching significance (P less than 0.05). When whole platelets and platelet membranes were stained with Coomassie blue or Periodic Acid-Schiff's reagent after electrophoresis in polyacrylamide gels no obvious alterations to major membrane constituents were observed on days 1 and 5 of storage. Paired in vivo autologous studies in healthy volunteers using 111Indium-labelling were performed at the end of 5 d of storage. The UV-treated platelets gave satisfactory and equivalent results for recovery, half life and survival when compared to controls. We conclude that PC irradiated with UVL and stored for 5 d in DuPont Stericell containers appear suitable for transfusion and may prove to be nonimmunogenic. Further in vivo studies of haemostatic efficacy and recipient alloimmunization are now warranted.
Blood Platelets↗
Applications of ultraviolet light in the preparation of platelet concentrates.
Passenger lymphocytes in platelet concentrates (PCs) may induce the formation of lymphocytotoxic antibodies (LCTAbs) and subsequent refractoriness to platelet transfusions. Ultraviolet (UV) irradiation can prevent lymphocytes' acting as stimulator or responder cells in mixed-lymphocyte reactions (MLRs) and could theoretically prevent LCTAb formation in vivo. A system has been devised for the delivery of UV irradiation to PCs; platelet storage characteristics and MLRs were evaluated in UV-irradiated PCs harvested from healthy donors with the Haemonetics V50 and PCS cell separators. MLR and response to phytohemagglutinin stimulation were abolished by a dose of 3000 joules per m2 at a mean wavelength of 310 nm. Platelet aggregatory responses to adenosine diphosphate (ADP), ristocetin, collagen and epinephrine, hypotonic shock response, and pH showed no important differences when control PCs and PCs irradiated as above were compared during 5 days of storage in Fenwal PL-1240 packs. Lactate production during storage was significantly higher in UV-treated PCs (p less than 0.001), but values did not exceed 20 mmol per L. UV transmission at 310 nm in standard blood product containers, including the Fenwal PL-146, PL-1240, and PL-732, was low (less than 30%), but it was acceptable in the Delmed Cryostorage and DuPont SteriCell packs (greater than 50%). UV irradiation may provide a simple and inexpensive means of producing nonimmunogenic PCs.
Blood Platelets↗
Development of lymphocytotoxic and platelet reactive antibodies: a prospective study in patients with acute leukaemia.
Lymphocytotoxic (LCT) and platelet reactive (PR) antibody (Ab) responses were serially determined in 49 patients with acute leukaemia. LCTAb were found in 20 patients and occurred in 13 patients with acute myeloid leukaemia and 7 patients with acute lymphoblastic leukaemia. Four differing patterns of LCTAb responses could be defined. Thirteen of 22 subjects showed marked reduction or loss of LCTAb. Indirect platelet immunofluorescence, measured by flow cytometry, provided the most convenient means of detecting PRAb which were found in 11 subjects and generally showed moderate or weak reactivity.
Adolescent↗
Lack of significant effect of therapeutic propranolol on measurable platelet function in healthy subjects.
Propranolol, a non-selective beta blocker, was administered orally in therapeutic doses. The effects of a single dose (160 mg) and one week's treatment (80 mg twice a day) on platelet function were compared in healthy young subjects. There were no significant changes in circulating platelet aggregates, template bleeding time, platelet factor 3 availability and thromboxane beta 2 (TX beta 2) generation. Platelet aggregation responses as assessed by angle of slope and maximal percentage aggregation (all agonists) and lag phase (collagen) showed no changes of biological importance, although minor changes reaching significance were observed with some agonists. These findings suggest that propranolol does not significantly affect platelet function when taken at doses commonly encountered in clinical practice.
Adolescent↗
Restoration of active haemopoiesis in a patient with myelofibrosis and subsequent termination in acute myeloblastic leukaemia: case report and review of the literature.
A patient with polycythaemia vera developed typical myelofibrosis after 15 yr. After a further 8 months, during which time she was pancytopenic and transfusion-dependent, a slow spontaneous recovery in haemopoiesis occurred and the full blood count became normal. 6 months later pancytopenia recurred and soon afterwards the patient developed acute myeloblastic leukaemia from which she died. The evolution of bone marrow morphology and isotopic studies. Only 2 previous reports of this kind of transformation exist in the literature, although restoration of normal or polycythaemic haemopoiesis has been reported in 8 patients with myelofibrosis. It is likely that these transformations occur because of alterations in stem cell behaviour rather than as a result of therapy.
Acute Disease↗
Pulmonary aspergillosis in immunosuppressed patients with haematological malignancies.
Invasive pulmonary aspergillosis as a cause of mortality and morbidity in patients with haematological malignancies is becoming more common. Predisposing factors are powerful immunosuppressive chemotherapy, neutropenia and synergistic combinations of antibiotics of great potency and wide spectrum of activity. Clinical and radiological signs are heterogeneous, sometimes misleading and often absent. Treatment is often empirical on suspicion alone. Amphotericin B is the only effective drug but it has marked toxicity, mainly renal. Infection is usually fatal without adequate treatment. This paper describes eight cases of invasive pulmonary aspergillosis seen in one centre in two years, reviews the literature and assesses associated problems.
Adolescent↗
The myelodysplastic syndromes--a study of haemostatic function and platelet ultrastructure.
The myelodysplastic syndromes (MDS) are characterised by dysplastic marrow and cytopenia. Clinically detectable bleeding is uncommon and usually attributed to thrombocytopenia. We have investigated some aspects of haemostatic function in 17 patients with MDS and compared the results with findings from 17 control patients matched for age and sex. No specific disorder of blood coagulation or fibrinolysis was identified. The main abnormalities observed in the patients were: prolongation of the bleeding time which was greater than could be explained on the basis of thrombocytopenia in 13 patients; absent, or severely impaired platelet aggregation in response to collagen in 7 patients; impaired platelet production of malondialydehyde when stimulated with collagen and abnormal release of 14C-5 hydroxytryptamine in 5 patients; and abnormalities of ultrastructure in all 5 patients whose platelets were viewed by electron microscopy.
Aged↗