Prothrombin complex concentrate vs. fresh frozen plasma in adult patients undergoing heart surgery - a pilot randomised controlled trial (PROPHESY trial).

There is equipoise regarding the use of prothrombin complex concentrate vs. fresh frozen plasma in bleeding patients undergoing cardiac surgery. We performed a pilot randomised controlled trial to determine the recruitment rate for a large trial, comparing the impact of prothrombin complex concentrate vs. fresh frozen plasma on haemostasis (1 h and 24 h post-intervention), and assessing safety. Adult patients who developed bleeding within 24 h of cardiac surgery that required coagulation factor replacement were randomly allocated to receive prothrombin complex concentrate (15 IU.kg-1 based on factor IX) or fresh frozen plasma (15 ml.kg-1 ). If bleeding continued after the first administration of prothrombin complex concentrate or fresh frozen plasma administration, standard care was administered. From February 2019 to October 2019, 180 patients were screened, of which 134 (74.4% (95%CI 67-81%)) consented, 59 bled excessively and 50 were randomly allocated; 25 in each arm, recruitment rate 35% (95%CI 27-44%). There were 23 trial protocol deviations, 137 adverse events (75 prothrombin complex concentrate vs. 62 fresh frozen plasma) and 18 serious adverse events (5 prothrombin complex concentrate vs. 13 fresh frozen plasma). There was no increase in thromboembolic events with prothrombin complex concentrate. No patient withdrew from the study, four were lost to follow-up and two died. At 1 h after administration of the intervention there was a significant increase in fibrinogen, Factor V, Factor XII, Factor XIII, α2 -antiplasmin and antithrombin levels in the fresh frozen plasma arm, while Factor II and Factor X were significantly higher in the prothrombin complex concentrate group. At 24 h, there were no significant differences in clotting factor levels. We conclude that recruitment to a larger study is feasible. Haemostatic tests have provided useful insight into the haemostatic changes following prothrombin complex concentrate or fresh frozen plasma administration. A definitive trial is needed to ascertain the benefits and safety for each.

Safety of blood donation from individuals with treated hypertension or non-insulin dependent type 2 diabetes - a systematic review.

BACKGROUND AND OBJECTIVES: This systematic review was aimed at finding evidence for the safety of blood donation by individuals with treated hypertension or type 2 diabetes. It was undertaken as part of a wider project to re-evaluate exclusion criteria for UK blood donors with a view to increasing eligibility. MATERIALS AND METHODS: Searches were undertaken in the Cochrane Library to 2008, MEDLINE (1950 onwards), EMBASE (1974 onwards), CINAHL (1982 onwards), BNID (1994 onwards), the NHSBT SRI Handsearching Database and the Web of Science (all years) to February 2008. Planned analysis was largely descriptive. RESULTS: We identified only 16 relevant papers. None of the identified studies directly addressed the review questions and methodological appraisal highlighted a number of deficiencies. However all included papers provided contributory data and the findings were consistent. No study found any evidence of increased risk to homologous (allogeneic) or autologous blood donors with treated hypertension or with raised baseline systolic blood pressure up to 200 mmHg. We found very few data relating to blood donation by diabetic subjects. CONCLUSIONS: No identified study indicated that raised baseline blood pressure level, treated hypertension or diabetes was predictive of increased adverse reactions in blood donors but the level of overall evidence was limited. This is the first attempt to systematically review a donor area as part of an approach to change longstanding practice recommendations, and may have implications for other recommendations for changes in donor acceptance criteria.

Oral deferiprone for iron chelation in people with thalassaemia.

BACKGROUND: Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through transfusions of red blood cells. Repeated transfusions result in excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. A commonly used iron chelator, deferiprone, has been found to be pharmacologically efficacious. However, important questions exist about the efficacy and safety of deferiprone compared to another iron chelator, desferrioxamine. OBJECTIVES: To summarise data from trials on the clinical efficacy and safety of deferiprone and to compare the clinical efficacy and safety of deferiprone for thalassaemia with desferrioxamine. SEARCH STRATEGY: We searched the Group's Haemoglobinopathies Trials Register, MEDLINE, EMBASE, Biological Abstracts, ZETOC, Current Controlled Trials and bibliographies of relevant publications. We contacted the manufacturers of deferiprone and desferrioxamine. Most recent searches: June 2006. SELECTION CRITERIA: Randomised controlled trials comparing deferiprone with another iron chelator; or comparing two schedules of deferiprone, in people with transfusion-dependent thalassaemia. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Missing data were requested from the original investigators. MAIN RESULTS: Ten trials involving 398 people (range 10 to 144 people) were included. Nine trials compared deferiprone with desferrioxamine or a combination of deferiprone and desferrioxamine and one compared different schedules of deferiprone. There was little consistency between outcomes and little information to fully assess the methodological quality of most of the included trials. No trial reported long-term outcomes (mortality and end organ damage). There was no consistent effect on reduction of iron overload between all treatment comparisons, with the exception of urinary iron excretion in comparisons of deferiprone with desferrioxamine. An increase in iron excretion levels favoured deferiprone in one trial and desferrioxamine in three trials, even though measurement of urinary iron excretion underestimates total iron excretion by desferrioxamine.Adverse events were recorded in trials comparing deferiprone with desferrioxamine. There was evidence of adverse events in all treatment groups. Adverse events in one trial were significantly more likely with deferiprone than desferrioxamine, relative risk 2.24 (95% confidence interval 1.19 to 4.23). AUTHORS' CONCLUSIONS: We found no reason to change current treatment recommendations, namely deferiprone is indicated for treating iron overload in people with thalassaemia major when desferrioxamine is contraindicated or inadequate. However, there is an urgent need for adequately-powered, high quality trials comparing the overall clinical efficacy and long-term outcome of deferiprone with desferrioxamine.

A systematic review and economic evaluation of epoetin alpha, epoetin beta and darbepoetin alpha in anaemia associated with cancer, especially that attributable to cancer treatment.

OBJECTIVES: To assess the effectiveness and cost-effectiveness of epoetin alpha, epoetin beta and darbepoetin alpha (referred to collectively in this report as epo) in anaemia associated with cancer, especially that attributable to cancer treatment. DATA SOURCES: Electronic databases were searched from 2000 (1996 in the case of darbepoetin alpha) to September 2004. REVIEW METHODS: Using a recently published Cochrane review as the starting point, a systematic review of recent randomised controlled trials (RCTs) comparing epo with best standard was conducted. Inclusion, quality assessment and data abstraction were undertaken in duplicate. Where possible, meta-analysis was employed. The economic assessment consisted of a systematic review of past economic evaluations, an assessment of economic models submitted by the manufacturers of the three epo agents and development of a new individual sampling model (the Birmingham epo model). RESULTS: In total 46 RCTs were included within this systematic review, 27 of which had been included in the Cochrane systematic review. All 46 trials compared epo plus supportive care for anaemia (including transfusions), with supportive care for anaemia (including transfusions), alone. Haematological response (defined as an improvement by 2 g/dl(-1)) had a relative risk of 3.4 [95% confidence interval (CI) 3.0 to 3.8, 22 RCTs] with a response rate for epo of 53%. The trial duration was most commonly 16-20 weeks. There was little statistical heterogeneity in the estimate of haematological response, and there were no important differences between the subgroups examined. Haemoglobin (Hb) change showed a weighted mean difference of 1.63 g/dl(-1) (95% CI 1.46 to 1.80) in favour of epo. Treatment with erythropoietin in patients with cancer-induced anaemia reduces the number of patients who receive a red blood cell transfusion (RBCT) by an estimated 18%. Health-related quality of life (HRQoL) data were analysed using vote counting and qualitative assessment and a positive effect was observed in favour of an improved HRQoL for patients on epo. Published information on side-effects was of poor quality. New trials provided further evidence of side-effects with epo, particularly thrombic events, but it is still unclear whether these could be accounted for by chance alone. The results of the previous Cochrane review had suggested a survival advantage for epo (HR 0.84, 95% CI 0.69 to 1.02), based on 19 RCTs. The update, based on 28 RCTs, suggests no difference (HR 1.03, 95% CI 0.88 to 1.21). Subgroup analysis suggested some explanations for this heterogeneity, but it is difficult to draw firm conclusions without access to the substantial amounts of missing or unpublished data, or more detailed results from some of the trials with heterogeneous patient populations. The conclusions are, however, broadly in line with those of a Food and Drug Administration (FDA) safety briefing, which recommended that patients with a haemoglobin above 12 g/dl(-1) should not be treated; the target rate of rise in Hb should not be too great, and further carefully conducted trials are required to determine which subgroups of patients may be harmed by the use of these products, in particular through the stimulation of tumour activity. Five published economic evaluations identified from the literature had inconsistent results, with estimates ranging from a cost per quality-adjusted life-year (QALY) under pound 10,000 through to epo being less effective and more costly than standard care. The more favourable evaluations assumed a survival advantage for epo. The three company models submitted each relied on assumed survival gains to achieve relatively low cost per QALY, from pound 13,000 to pound 28,000, but generated estimates from pound 84,000 to pound 159,000 per QALY when no survival gain was assumed. Each of these models relied on Hb levels alone driving utility, and each assumed gradual normalisation of Hb in the standard treatment arm after the end of treatment. The Birmingham epo model followed the company models in regard to the relationship between Hb levels and utility, and also assumed normalisation in the base case. With no survival gain, the incremental cost per QALY was pound 150,000, falling to pound 40,000 when the lower, more favourable, confidence interval for survival was used. CONCLUSIONS: Epo is effective in improving haematological response and reducing RBCT requirements, and appears to have a positive effect on HRQoL. The incidence of side-effects and effects on survival remains highly uncertain. However, if there is no impact on survival, it seems highly unlikely that epo would be considered a cost-effective use of healthcare resources. The main target for further research should be improving estimates of impact on survival, initially through more detailed secondary research, such as the individual patient data meta-analysis started by the Cochrane group. Further trials may be required, and have been recommended by the FDA, although many trials are in progress, completed but unreported or awaiting mature follow-up. The Birmingham epo model developed as part of this project contains new features that improve its flexibility in exploring different scenarios; further refinement and validation would therefore be of assistance. Finally, further research to resolve uncertainty about other parameters, particularly quality of life, adverse events, and the rate of normalisation, would also be beneficial.

Cost-effectiveness of using prognostic information to select women with breast cancer for adjuvant systemic therapy.

OBJECTIVES: To investigate the cost-effectiveness of using prognostic information to identify patients with breast cancer who should receive adjuvant therapy. DATA SOURCES: Electronic databases from 1980 through to February 2002. A survey of clinical practice in UK cancer centres and units. Large retrospective dataset containing data on prognostic factors, treatments and outcomes for women with early breast cancer treated in Oxford. REVIEW METHODS: Between six and nine databases were searched by an information expert. Evidence-based methods were used to review and select those studies and the quality of each included paper was assessed using standard assessment tools reported in the literature or piloted and developed for this study. A survey of clinical practice in UK cancer centres and units was carried out to ensure that conclusions drawn from the report could be implemented. These data, along with the information gathered in the systematic reviews, informed the methodological approach adopted for the health economic modelling. An illustrative framework was developed for incorporating patient-level prediction within a health economic decision model. This framework was applied to a large retrospective dataset containing data on prognostic factors, treatments and outcomes for women with early breast cancer treated in Oxford. The data were used to estimate directly a parametric regression-based risk equation, from which a prognostic index was developed, and prognosis-specific estimates of the baseline breast cancer hazard could be observed. Published estimates of treatment effects, health service treatment costs and utilities were used to construct a decision analytic framework around this risk equation, thus enabling simulation of the effectiveness and cost-effectiveness of adjuvant therapy for all possible combinations of prognostic factors included in the model. RESULTS: The lack of good-quality systematic reviews and well-conducted studies of prognostic factors in breast cancer is a striking finding. There are no registers of studies of prognostic factors or of reviews of prognostic studies. Many of the reviews used weak methods, primary studies are similar with poor methodology and reporting of results. In addition, there is much variation in patient populations, assay methods, analysis of results, definitions used and reporting of results. Most studies appear to be retrospective and some use inappropriate methods likely to inflate outcomes such as optimising cut points and failing to test the results in an independent population. Very few reviews used meta-analysis to conduct a pooled analysis and to provide an estimate of the average size of any association. Instead, most reviews relied on vote counting. Although many prognostic models for breast cancer have been published, remarkably few have been re-examined by independent groups in independent settings. The few validation studies have been carried out on ill-defined samples, sometimes of smaller size and short follow-up, and sometimes using different patient outcomes when validating a model. The evidence from the validation studies shows support for the prognostic value of the Nottingham Prognostic Index (NPI). No new prognostic factors have been shown to add substantially to those identified in the 1980s. Improvement of this index depends on finding factors that are as important as, but independent of, lymph node, stage and pathological grade. The NPI remains a useful clinical tool, although additional factors may enhance its use. We accepted that hormone receptor status (ER) for hormonal therapy such as tamoxifen and prediction of response to trastuzumab by HER2 did not require systematic review, as the mechanism of action of these drugs requires intact receptors. There was no clear evidence that other factors were useful predictors of response and survival. The survey confirmed pathological nodal status, tumour grade, tumour size and ER status as the most clinically important factors for consideration when selecting women with early breast cancer for adjuvant systemic therapy in the UK. The protocols revealed that although UK cancer centres appear to be using the same prognostic and predictive factors when selecting women to receive adjuvant therapy, much variation in clinical practice exists. Some centres use protocols based upon the NPI whereas others do not use a single index score. Within NPI and non-NPI users, between-centre variability exists in guidelines for women for whom the benefits are uncertain. Consensus amongst units appears to be greatest when selecting women for adjuvant hormone therapy with the decision based primarily upon ER or progesterone receptor status rather than combinations of a number of factors. Guidelines as to who should receive adjuvant chemotherapy, however, were found to be much less uniform. Searches of the literature revealed only five published papers that had previously examined the cost-effectiveness of using prognostic information for clinical decision-making. These studies were of varying quality and highlight the fact that economic evaluation in this area appears still to be in its infancy. By combining methodologies used in determining prognosis with those used in health economic evaluation, it was possible to illustrate an approach for simulating the effectiveness (survival and quality-adjusted survival) and the cost-effectiveness associated with the decision to treat individual women or groups of women with different prognostic characteristics. The model showed that effectiveness and cost-effectiveness of adjuvant systemic therapy have the potential to vary substantially depending upon prognosis. For some women therapy may prove very effective and cost-effective, whereas for others it may actually prove detrimental (i.e. the reductions in health-related quality of life outweigh any survival benefit). CONCLUSIONS: Outputs from the framework constructed using the methods described here have the potential to be useful for clinicians, attempting to determine whether net benefits can be obtained from administering adjuvant therapy for any presenting woman; and also for policy makers, who must be able to determine the total costs and outcomes associated with different prognosis based treatment protocols as compared with more conventional treat all or treat none policies. A risk table format enabling clinicians to look up a patient's prognostic factors to determine the likely benefits (survival and quality-adjusted survival) from administering therapy may be helpful. For policy makers, it was demonstrated that the model's output could be used to evaluate the cost-effectiveness of different treatment protocols based upon prognostic information. The framework should also be valuable in evaluating the likely impact and cost-effectiveness of new potential prognostic factors and adjuvant therapies.

Erythropoietin or darbepoetin for patients with cancer.

BACKGROUND: Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (Epo), darbepoetin (Darbepo) and red blood cell transfusions. OBJECTIVES: The aim of this systematic review was to assess the effects of Epo or Darbepo to either prevent or treat anaemia in cancer patients. SEARCH STRATEGY: We searched the Central Register of Controlled Trials, MEDLINE and EMBASE and other data bases. Searches were done for the periods 01/1985 to 12/2001 for the first review and 1/2002 to 04/2005 for the update. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials on managing anaemia in cancer patients that compared the use of Epo/Darbepo (plus transfusion if needed) with observation until red blood cell transfusion was required. DATA COLLECTION AND ANALYSIS: Several reviewers independently assessed trial quality and extracted data. MAIN RESULTS: This update of the systematic review included a total of 57 trials with 9,353 patients. Of these, 27 trials with 3,287 adults were also included in the first Cochrane Review. Thirty trials with 6,066 patients were added during the update process. Use of Epo/Darbepo significantly reduced the relative risk of red blood cell transfusions (RR 0.64; 95% CI 0.60 to 0.68, 42 trials, n = 6,510). On average participants in the Epo/Darbepo group received one unit of blood less than the control group (WMD -1.05; 95% CI -1.32 to -0.78, 14 trials, n = 2,353). For participants with baseline haemoglobin below 12 g/dL haematological response was observed more often in participants receiving Epo/Darbepo (RR 3.43; 95% CI 3.07 to 3.84, 22 trials, n = 4,307). There was suggestive evidence that Epo/Darbepo may improve Quality of Life (QoL). The relative risk for thrombo embolic complications was increased in patients receiving Epo/Darbepo compared to controls (RR 1.67, 95% CI 1.35 to 2.06; 35 trials, n = 6,769). Uncertainties remain whether and how Epo/Darbepo effects tumour response (fixed effect RR 1.12; 95% CI 1.01 to 1.23, 13 trials, n = 2,833; random effects: RR 1.09; 95% CI 0.94 to 1.26) or overall survival (unadjusted and adjusted data: HR 1.08; 95% CI 0.99 to 1.18; 42 trials, n = 8,167). AUTHORS' CONCLUSIONS: There is consistent evidence that administration of Epo/Darbepo reduces the relative risk for blood transfusions and the number of units transfused in cancer patients. For patients with baseline haemoglobin below 12 g/dL (mild anaemia) there is strong evidence that Epo/Darbepo improves haematological response. There is suggestive evidence that Epo/Darbepo may improve QoL. However, there is strong evidence that Epo/Darbepo increases the relative risk for thrombo embolic complications. Whether and how Epo/Darbepo effects tumour response and overall survival remains uncertain.

Platelet transfusion prophylaxis for patients with haematological malignancies: where to now?

National guidelines for platelet transfusion in many countries recommend that the general platelet transfusion trigger for prophylaxis is 10x10(9)/l. This annotation reviews the evidence for this threshold level and discusses other current unresolved issues relevant to platelet transfusion practice such as the optimal dose and the clinical benefit of a strategy for the prophylactic use of platelet transfusions when the platelet count falls below a given threshold.

Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalassaemia.

BACKGROUND: Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through transfusions of red blood cells. Repeated transfusions results in excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. Desferrioxamine is the most widely used iron chelator. Substantial data have shown the beneficial effects of desferrioxamine. However, important questions exist about whether desferrioxamine is the best schedule for iron chelation therapy. OBJECTIVES: To determine the effectiveness (dose and method of administration) of desferrioxamine in people with transfusion-dependent thalassaemia. SEARCH STRATEGY: We searched the Cochrane Haemoglobinopathies Trials Register, MEDLINE, EMBASE, ZETOC, Current Controlled Trials and bibliographies of relevant publications. We also contacted the manufacturers of desferrioxamine and other iron chelators. Date of last searches: April 2004. SELECTION CRITERIA: Randomised controlled trials comparing desferrioxamine with placebo; with another iron chelator; or comparing two schedules of desferrioxamine, in people with transfusion-dependent thalassaemia. DATA COLLECTION AND ANALYSIS: Four authors working independently, were involved in trial quality assessment and data extraction. Missing data were requested from the original investigators. MAIN RESULTS: Eight trials involving 334 people (range 20 to 144 people) were included. One trial compared desferrioxamine with placebo, five compared desferrioxamine with another iron chelator (deferiprone) and two compared different schedules of desferrioxamine. Overall, few trials measured the same outcomes.Compared to placebo, desferrioxamine significantly reduced iron overload. The number of deaths at 12 years follow up and evidence of reduced end-organ damage was less for desferrioxamine than placebo. When desferrioxamine was compared to deferiprone or a different desferrioxamine schedule there were no statistically significant differences in measures of iron overload. Compliance was recorded by two trials. Compliance was less for desferrioxamine than deferiprone in one trial and of no difference in comparison with desferrioxamine and deferiprone combined with a second trial. Adverse events were recorded in trials comparing desferrioxamine with other iron chelators. There was evidence of adverse events in all treatment groups. In one trial, adverse events were significantly less likely with desferrioxamine than deferiprone, relative risk 0.45 (95% confidence interval 0.24 to 0.84). Assessment of the methodological quality of included trials was not possible, given the general absence of these data in the trials. AUTHORS' CONCLUSIONS: We found no reason to change current treatment recommendations. However, considerable uncertainty continues to exist about the optimal schedule for desferrioxamine in people with transfusion-dependent thalassaemia.

Prophylactic platelet transfusion for haemorrhage after chemotherapy and stem cell transplantation.

BACKGROUND: Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in thrombocytopenic patients with bone marrow failure. Although considerable advances have been made in platelet transfusion therapy in the last 30 years, some areas continue to provoke debate, especially the use of prophylactic platelet transfusions for the prevention of thrombocytopenic bleeding. OBJECTIVES: To determine the optimal use of platelet transfusion for the prevention of haemorrhage (prophylactic platelet transfusion) in patients with haematological malignancies undergoing chemotherapy or stem cell transplantation. SEARCH STRATEGY: Randomised controlled trials (RCTs) were searched for in the Cochrane Central Register of Controlled Trials (CENTRAL). Searching was also undertaken on the OVID versions of MEDLINE and EMBASE using an RCT search filter strategy. SELECTION CRITERIA: Randomised controlled trials involving transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given prophylactically to prevent bleeding in patients with haematological malignancies and receiving treatment with chemotherapy and/or stem cell transplantation. DATA COLLECTION AND ANALYSIS: All electronically derived citations and abstracts of papers identified by the review search strategy were initially screened for relevancy by one reviewer. Studies clearly irrelevant were excluded at this stage. The full text of all potentially relevant trials was then formally assessed for eligibility by two reviewers independently. Two reviewers completed data extraction independently. Missing data were requested from the original investigators, as appropriate. Disagreements were resolved by discussion with the other reviewers. MAIN RESULTS: Eight completed published trials, with a total of 390 participants in the intervention groups and 362 participants in the control groups, were included in the review for further analysis. The eight studies were classified as: * three trials relevant to prophylactic platelet transfusions versus therapeutic platelet transfusions; * three trials relevant to prophylactic platelet transfusion with one trigger level versus prophylactic platelet transfusion with another trigger level; * two trials relevant to prophylactic platelet transfusion with one dose schedule versus prophylactic platelet transfusion with another dose schedule. The few reports of controlled trials addressing prophylactic versus therapeutic transfusions contained small numbers of patients and were all undertaken over 25 years ago. None of these three studies explicitly clarified whether the lack of a reported difference was a reflection of insufficient power in the trials. The findings of the meta-analyses for this group of three small studies must be interpreted with caution. In contrast, more contemporary trials addressed the question of what platelet count thresholds should apply for prophylactic transfusion; three identified studies broadly compared platelet transfusion thresholds of 10 versus 20 x 109/litre for different clinical groups of patients. There were no statistically significant differences between the groups with regards to mortality, remission rates, number of participants with severe bleeding events or red cell transfusion requirements. However, it was unclear whether the studies had sufficient power to demonstrate in combination non-inferiority in terms of safety of the lower threshold, 10 x 109/litre. Insufficient randomised trials have been undertaken to make clinically relevant conclusions about the effect of different platelet doses. REVIEWERS' CONCLUSIONS: There are no reasons to change current practice but uncertainty about the practice of prophylactic transfusion therapy should be recognised, particularly in the light of concerns about the scenario that blood products, including platelets, could become an increasingly scarce resource in the future and for which adequate alternatives do not exist. Consideration should be given to developing adequately powered trials comparing strategies of prophylaxis versus therapeutic platelet transfusion.

Treatment of myelodysplasia with oral cyclosporin.

Recent studies have shown a good response to immunosuppressive treatment with cyclosporin A (CSA) in patients with the myelodysplastic syndrome (MDS). We have treated six transfusion-dependent MDS patients with CSA for a minimum of 3 months. None of these patients showed a significant response, while the drug was withdrawn in 3/6 patients because of intolerable side-effects. Two reasons for the failure of this treatment in our patients can be advanced. Firstly, the hypoplastic variant of MDS predominated in previous studies in contrast to ours. Secondly, the concomitant use of other immunosuppressive agents in previous studies might have enhanced the effect of CSA. We suggest further therapeutic trials of CSA in MDS, selecting patients on the basis of in vitro studies that predict an immunological basis for their disease, to assess its efficacy in prolonging survival.

Platelet activation via the collagen receptor GPVI is not altered in platelets from chronic myeloid leukaemia patients despite the presence of the constitutively phosphorylated adapter protein CrkL.

In this study, we show that the adapter proteins CrkL and Cbl undergo increases in tyrosine phosphorylation and form an intracellular complex in platelets stimulated with the snake venom toxin convulxin, a selective agonist at the collagen receptor glycoprotein VI (GPVI). Constitutive tyrosine phosphorylation of CrkL has previously been reported in platelets from chronic myeloid leukaemia (CML) patients. This was confirmed in the present study, and shown to result in a weak constitutive association of CrkL with Cbl and a number of other unidentified tyrosine-phosphorylated proteins. There was no further increase in phosphorylation of CrkL in CML platelets in response to GPVI activation, whereas phosphorylation of Cbl and its association with CrkL were potentiated. In addition, this was accompanied by a small increase in p42/ 44 mapkinase (MAPK) activity in CML platelets. The functional consequence of the presence of constitutively phosphorylated proteins in CML platelets was investigated by measurement of aminophospholipid exposure and alpha-granule secretion. This revealed little alteration in the concentration-response curves for either in CML platelets stimulated via GPVI, although maximal levels of P-selectin were depressed. Despite the minimal effect on platelet activation in CML patients, we cannot exclude a role for CrkL or Cbl in signal transduction pathways stimulated via GPVI.