Irwin Walker

The Role of the Plasma from Platelet Concentrates in Transfusion Reactions

BACKGROUND Febrile, nonhemolytic transfusion reactions are the most frequent adverse reactions to platelets. A number of observations argue against the widely held view that these reactions result from the interaction between antileukocyte antibodies in the recipient and leukocytes in the platelet product. We sought to determine whether substances in the plasma or the cells in the product cause reactions to transfused platelets. METHODS We separated standard platelet concentrates into their plasma and cellular components and then transfused both portions in random order. Patients were monitored for reactions during all transfusions. Before each transfusion, the concentration of cytokines (interleukin-1 beta and interleukin-6) was measured in the platelet products. Studies were also performed on the platelet products to determine the effect of storage on the concentration of cytokines. RESULTS Sixty-four pairs of platelet-product components (the plasma supernatant and the cells) were administered to 12 patients. There were 20 reactions to the plasma supernatant and 6 reactions to the cells (chi-square = 6.50, P = 0.009). Eight transfusions were associated with reactions to both products. The plasma component was more likely to cause severe reactions than the cells (chi-square = 9.6, P < 0.01). A strong positive correlation was observed between the reactions and the concentration of interleukin-1 beta and interleukin-6 in the plasma supernatant (P < 0.001 and P = 0.034, respectively). In vitro studies demonstrated that interleukin-1 beta and interleukin-6 concentrations rise progressively in stored platelets and that these concentrations are related to the leukocyte count in the platelet product. CONCLUSIONS Bioreactive substances in the plasma supernatant of the platelet product cause most febrile reactions associated with platelet transfusions. Removing the plasma supernatant before transfusion can minimize or prevent these reactions.

Impedance plethysmography using the occlusive cuff technique in the diagnosis of venous thrombosis.

Impedance plethysmography using the cuff technique has been compared with venography in 346 consecutive patients with suspected venous thromboembolism. The limbs were classified according to the venographic results as no thrombosis, proximal (popliteal, femoral, or iliac) vein thrombosis, and calf thrombosis. A discriminant analysis was performed. The impedance plethysmographic result was normal in 386 of 397 limbs which were normal on venography, a specificity of 97%, and abnormal in 124 of 133 limbs which showed proximal vein thrombosis, a sensitivity of 93%. Seventy-three of 88 limbs with calf vein thrombi had a normal impedance plethysmographic result. The sensitivity in 29 limbs with asymptomatic proximal vein thrombosis was 83%. Impedance plethysmography is an accurate method for detecting proximal vein thrombosis but has limitations which include the possibility of false positive results due to arterial insufficiency and muscle tension.

A randomized controlled trial comparing the frequency of acute reactions to plasma-removed platelets and prestorage WBC-reduced platelets

BACKGROUND: Removal of the plasma supernatant from platelets before transfusion is effective in preventing acute reactions to platelets caused by cytokines. Prestorage WBC reduction of platelets may be even more effective at preventing reactions as the WBCs are removed and WBC‐derived cytokines do not accumulate in this component. This study evaluates the effectiveness of plasma removal and two methods of prestorage WBC reduction for preventing acute reactions to platelets.

Combined use of leg scanning and impedance plethysmography in suspected venous thrombosis. An alternative to venography.

Venography is the standard method for the diagnosis of venous thrombosis but is invasive and may cause discomfort. We evaluated the combination of impedance plethysmography and 125I-fibrinogen leg scanning as an alternative to venography in 200 symptomatic patients. One or both of these less invasive tests was positive in 81 of 86 patients with positive venograms (sensitivity of 94 per cent) and both were negative in 104 of 114 patients with negative venograms (specificity of 91 per cent). These two tests detected all 60 patients with popliteal or more proximal venous thrombosis and 21 of 26 patients with calf-vein thrombosis. In addition, this approach detected 21 of 22 patients with calf-vein thrombosis with symptoms for eight days or less. These results suggest that the combination of these two less invasive tests can be used as an alternative to venography in selected patients with clinically suspected venous thrombosis.

A review of randomized controlled trials comparing the effectiveness of hand held computers with paper methods for data collection

BackgroundHandheld computers are increasingly favoured over paper and pencil methods to capture data in clinical research.MethodsThis study systematically identified and reviewed randomized controlled trials (RCTs) that compared the two methods for self-recording and reporting data, and where at least one of the following outcomes was assessed: data accuracy; timeliness of data capture; and adherence to protocols for data collection.ResultsA comprehensive key word search of NLM Gateways database yielded 9 studies fitting the criteria for inclusion. Data extraction was performed and checked by two of the authors. None of the studies included all outcomes. The results overall, favor handheld computers over paper and pencil for data collection among study participants but the data are not uniform for the different outcomes. Handheld computers appear superior in timeliness of receipt and data handling (four of four studies) and are preferred by most subjects (three of four studies). On the other hand, only one of the trials adequately compared adherence to instructions for recording and submission of data (handheld computers were superior), and comparisons of accuracy were inconsistent between five studies.ConclusionHandhelds are an effective alternative to paper and pencil modes of data collection; they are faster and were preferred by most users.

A randomized controlled trial comparing plasma removal with white cell reduction to prevent reactions to platelets.

BACKGROUND: Recent data suggest that most reactions to platelets are caused by white cell (WBC)‐derived cytokines that accumulate in the plasma portion of the component during storage. On the basis of this theory, the effectiveness of two interventions to prevent reactions, poststorage WBC reduction and plasma depletion, were compared.

Impedance plethysmography: the relationship between venous filling and sensitivity and specificity for proximal vein thrombosis.

We investigated the hypothesis that the diagnostic accuracy of impedance plethysmography (IPG) for thrombosis of the popliteal or more proximal veins increases with enhanced venous filling. Venous filling was increased by prolonging cuff occlusion and by sequential testing. IPG and vengography were performed on 169 legs with and 317 legs without proximal vein thrombosis. The sensitivity and specificity of IPG rose significantly with increased venous filling. Changes in venous filling were associated with corresponding changes in emptying in normal legs, but not those with proximal vein thrombosis, so that the regression lines relating venous filling and emptying in normal and abnormal legs diverged significantly (P less than 0.001). If the IPG sequence had been terminated after only a single 45 second occlusion time test, sensitivity would have deteriorated by 10% and specificity by 20%. These observations indicate that the accuracy of IPG can be significantly enhanced if optimal venous filling is obtained.

Validation and extension of the EBMT Risk Score for patients with chronic myeloid leukaemia (CML) receiving allogeneic haematopoietic stem cell transplants.

The European Group for Blood and Marrow Transplantation (EBMT) devised a scoring system to predict survival after allogeneic haematopoietic stem cell transplantation (HSCT) for chronic myeloid leukaemia (CML). The present International Bone Marrow Transplant Registry study of 3211 patients tested the EBMT Risk Score in a independent population, investigated the value of adding other variables, evaluated a new risk score specifically for chronic phase and compared the allograft risk scores with risk scores established by Sokal in 1984 and Hasford in 1998 for survival with non‐transplant treatments. The primary outcome was 5‐year survival after HSCT; survival curves, regression models and measurements of explained variation were used to compare scores. Using the EBMT scoring system, survival in the independent dataset was almost identical to those in the original EBMT publication, thus validating the EBMT Risk Score. Adding one extra variable, performance status, or designing a score specifically for early chronic phase by using the original five variables with different breakpoints gave results only slightly better than the original EBMT Score. Sokal and Hasford Scores did not predict survival after HSCT. We concluded that the EBMT Risk Score does not currently require modification.

Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial

BACKGROUND Pretreatment with anti-thymocyte globulin (ATG) decreases the occurrence of chronic graft-versus-host disease (CGVHD) after haemopoietic cell transplantation from an unrelated donor, but evidence of patient benefit is absent. We did a study to test whether ATG provides patient benefit, particularly in reducing the need for long-term immunosuppressive treatment after transplantation. METHODS We did a phase 3, multicentre, open-label, randomised controlled trial at ten transplant centres in Canada and one in Australia. Eligible patients were aged 16 to 70 years with any haematological malignancy and a Karnofsky score of at least 60 receiving either myeloablative or non-myeloablative (or reduced intensity) conditioning preparative regimens before haemopoietic cell transplantation from an unrelated donor. We allocated patients first by simple randomisation (1:1), then by a minimisation method, to either pretransplantation rabbit ATG plus standard GVHD prophylaxis (ATG group) or standard GVHD prophylaxis alone (no ATG group). We gave a total dose of ATG of 4·5 mg/kg intravenously over 3 days (0·5 mg/kg 2 days before transplantation, 2·0 mg/kg 1 day before, and 2·0 mg/kg 1 day after). The primary endpoint was freedom from all systemic immunosuppressive drugs without resumption up to 12 months after transplantation. Analysis was based on a modified intention-to-treat method. This trial was registered at ISRCTN, number 29899028. FINDINGS Between June 9, 2010, and July 8, 2013, we recruited and assigned 203 eligible patients to treatment (101 to ATG and 102 to no ATG). 37 (37%) of 99 patients who received ATG were free from immunosuppressive treatment at 12 months compared with 16 (16%) of 97 who received no ATG (adjusted odds ratio 4·25 [95% CI 1·87-9·67]; p=0·00060. The occurrence of serious adverse events (Common Terminology Criteria grades 4 or 5) did not differ between the treatment groups (34 [34%] of 99 patients in the ATG group vs 41 [42%] of 97 in the no ATG group). Epstein-Barr virus reactivation was substantially more common in patients who received ATG (20 [one of whom died-the only death due to an adverse event]) versus those who did not receive ATG (two [no deaths]). No deaths were attributable to ATG. INTERPRETATION ATG should be added to myeloblative and non-myeloblative preparative regimens for haemopoietic cell transplantation when using unrelated donors. The benefits of decreases in steroid use are clinically significant. Epstein-Barr virus reactivation is increased, but is manageable by prospective monitoring and the use of rituximab. Future trials could determine whether the doses of ATG used in this trial are optimum, and could also provide additional evidence of a low relapse rate after non-myeloablative regimens. FUNDING The Canadian Institutes of Health Research and Sanofi.

High-dose cytosine arabinoside as the initial treatment of poor-risk patients with acute nonlymphocytic leukemia: a Leukemia Intergroup Study.

Sixty-seven patients with newly diagnosed acute nonlymphocytic leukemia (ANLL) who were considered to be poor candidates for treatment with cytosine arabinoside (ara-C)/anthracycline antibiotic therapy were treated with high-dose ara-C (HDara-C) remission induction therapy. Thirty-four of the 67 patients had a hematologic disorder before developing acute leukemia or had a history of exposure to marrow toxins, 23 patients were greater than 70 years old, and 10 patients had medical problems that were felt to be a contraindication to therapy with an anthracycline antibiotic. Forty-two percent of patients entered complete remission (CR), whereas 22% failed to enter remission because of persistent leukemia. Treatment was associated with substantial toxicity varying from nausea and vomiting to irreversible cerebellar toxicity. Thirty-four percent of patients died during therapy. Poor performance status, a low serum albumin, and a low platelet count were associated with death during remission induction therapy, whereas a high pretherapy leukemic cell mass and a large number of residual leukemic cells in the marrow after six days of therapy were associated with treatment failure due to persistent leukemia.