Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study.

BACKGROUND: Routine prophylactic platelet transfusion is the standard of care for patients with severe thrombocytopenia. We assessed the effect of a new strategy of therapeutic platelet transfusion on the number of transfusions and safety in patients with hypoproliferative thrombocytopenia. METHODS: We did a multicentre, open-label, randomised parallel-group trial at eight haematology centres in Germany. Patients aged 16-80 years, who were undergoing intensive chemotherapy for acute myeloid leukaemia or autologous haemopoietic stem-cell transplantation for haematological cancers, were randomly assigned via a computer-generated randomisation sequence to receive either platelet transfusion when bleeding occurred (therapeutic strategy) or when morning platelet counts were 10×10(9) per L or lower (prophylactic strategy). Investigators undertaking interventions were not masked to group assignment. The primary endpoint was the number of platelet transfusions. Analysis was by intention to treat. This trial is registered, NCT00521664. FINDINGS: 197 patients were assigned the prophylactic strategy and 199 the therapeutic strategy. Of 391 patients analysed, the therapeutic strategy reduced the mean number of platelet transfusions by 33·5% (95% CI 22·2-43·1; p<0·0001) in all patients (2·44 [2·22-2·67] in prophylactic group vs 1·63 [1·42-1·83] in therapeutic group), 31·6% (18·6-42·6; p<0·0001) in those with acute myeloid leukaemia (2·68 [2·35-3·01] vs 1·83 [1·58-2·10]), and 34·2% (6·6-53·7; p=0·0193) in those who had had autologous transplantation (1·80 [1·45-2·15] vs 1·18 [0·82-1·55]. We noted no increased risk of major haemorrhage in patients who had undergone autologous transplantation. In those with acute myeloid leukaemia, risk of non-fatal grade 4 (mostly CNS) bleeding was increased. We recorded 15 cases of non-fatal haemorrhage: four retinal in each transfusion group, and one vaginal and six cerebral in the therapeutic group. 12 patients died in the study: two from fatal cerebral haemorrhages in the therapeutic group, and ten (five in each treatment group) unrelated to major bleeding. INTERPRETATION: The therapeutic strategy could become a new standard of care after autologous stem-cell transplantation; however, prophylactic platelet transfusion should remain the standard for patients with acute myeloid leukaemia. The new strategy should be used by some haematology centres only if the staff are well educated and experienced in the new approach and can react in a timely way to first signs of CNS bleeding. FUNDING: Deutsche Krebshilfe eV (German Cancer Aid).

Low-dose alemtuzumab vs. standard policy for prevention of graft-versus-host disease in unrelated and related allogeneic stem cell transplantation-a matched pair analysis.

Antibody-mediated in vivo T cell depletion is common prior to unrelated (URD) or mismatched allogeneic stem cell transplantation (alloSCT) and optional in HLA-identical sibling (FAM) alloSCT. While anti-thymocyte globulin (ATG) is the current standard, alemtuzumab is an alternative. The optimal dose of alemtuzumab has not been defined. This retrospective analysis compares low-dose alemtuzumab with ATG in URD alloSCT and with no antibody in FAM alloSCT. Twenty-eight patients treated with alemtuzumab (10 mg; HLA mismatch, 20 mg) were matched to 28 patients who have either received ATG (URD) or no antibody (noAB) according to disease, disease stage, age, transplant type and risk state. Both groups were compared for engraftment, outcome, disease-free (DFS) and overall survival (OS), graft-versus-host disease (GvHD), freedom from GvHD (ffGvHD) and transplant-related mortality (TRM). No significant differences were found between the groups for leukocyte engraftment, GvHD, ffGvHD, TRM, DFS and OS. There was a trend for reduction of cGvHD by alemtuzumab (p = 0.05). A transplant-type stratified subanalysis consolidated equivalency of alemtuzumab and ATG in URD-SCT and indicates possible superiority of low-dose alemtuzumab compared to noAB in FAM-SCT. Low-dose alemtuzumab, as part of conditioning regimen prior to alloSCT, is safe and comparable to standard ATG. Prospective trials, particularly comparing alemtuzumab vs. noAB in FAM alloSCT, should be conducted.

Severe disseminated coagulopathy caused by adenocarcinoma with bone marrow metastasis.

BACKGROUND: Patients with mucin-producing adenocarcinoma have an increased risk for venous and arterial thrombosis. When these patients present with thrombocytopenia, disseminated intravascular coagulopathy (DIC) is often the underlying cause. CASE REPORT: We report 2 patients who were admitted due to bleeding symptoms of unknown cause, in whom further workup revealed adenocarcinoma-induced DIC. CONCLUSION: In elderly patients presenting with signs of DIC, such as reduced fibrinogen levels, elevated prothrombin time, elevated D-dimer, and thrombocytopenia, without any obvious reason (e.g., sepsis), adenocarcinoma-associated coagulopathy should be considered as the underlying cause. Paradoxically, in these patients bleeding symptoms improve when the patient is sufficiently anti-coagulated with low molecular weight heparin. Treatment of the underlying disease is of central importance in controlling acute or chronic DIC associated with malignant diseases and chemotherapy should be started as soon as possible.

Reduced platelet transfusions and earlier platelet engraftment using alemtuzumab-based conditioning regimen in allogeneic stem cell transplantation.

PURPOSE: In patients undergoing allogeneic stem cell transplantation, conditioning regimens containing alemtuzumab instead of anti-thymocyte globulin (ATG) may result in an earlier platelet engraftment and a reduced number of platelet transfusions. METHODS: We performed a retrospective, single-center, case-control study analyzing time to engraftment and transfusion needs using alemtuzumab in comparison with ATG as part of conditioning protocol. RESULTS: Median values for time to platelet engraftment, number of transfused platelet concentrates and number of transfused red cell concentrates were 12 versus 19.5 days (p < 0.001), 2 versus 14 (p < 0.001) and 6 versus 14.5 (p = 0.003) in the alemtuzumab and ATG group. Time to leukocyte engraftment did not differ with median 15 days in both groups. Patients in the ATG group showed a significant higher decrease in platelet count during conditioning (68 vs. 29 %, p = 0.001), leading to significant lower median platelet counts at the day of stem cell infusion (38 vs. 95.5 Gpt/l, p = 0.008), and higher values for median C-reactive protein after first antibody infusion (69.0 vs. 43.6 mg/l, p = 0.001) compared with alemtuzumab group. Test for significance was done by using Wilcoxon rank-sum test. Subgroup analysis considering the type of ATG used (Thymoglobulin vs. ATG Fresenius) revealed that differences between alemtuzumab and ATG group were more due to effects of ATG Fresenius than Thymoglobulin. CONCLUSIONS: The use of alemtuzumab in comparison with ATG as part of the conditioning regimen may be an approach to reduce the number of transfused platelet and red cell concentrates after allogeneic stem cell transplantation.

Heparin-induced thrombocytopenia in children: 12 new cases and review of the literature.

Immune-mediated heparin-induced thrombocytopenia (HIT) is a rare but severe adverse effect of heparin therapy. Only few data are available on clinical presentation, diagnosis and management of HIT in children. Records of all patients sent to our laboratory between 1995 and November 2003 were reviewed. To identify literature reports a Medline search was performed, the reference lists of those publications were screened and the abstracts of meetings on thrombosis and hemostasis between 2000 and 2003 were assessed. We identified 12 new HIT patients between 13 months and 18 years of age from our laboratory and 71 reports on HIT in children in the literature. For the assessment of frequency of HIT all studies enrolling > 100 patients were analyzed. HIT is rare in children. In pediatric patients, there seem to be two risk groups: newborns and infants under 4 years of age undergoing cardiac surgery (incidence approximately 1-2%), and teenagers treated with heparin for thrombosis. For confirmation of HIT in children, antigen assays are most important. There are conflicting data on the optimal cut-off, with one randomized, double-blind trial indicating that the cut-off established in adults is appropriate. There are no systematic studies on alternative anticoagulants in children affected by HIT. Most data are available for lepirudin and danaparoid. Substitution of unfractionated heparin by low-molecular-weight heparins for regular anticoagulation may reduce the incidence of HIT.

Diffuse alveolar hemorrhage with acute respiratory distress syndrome associated with phenprocoumon therapy.

An 84-year-old woman was admitted to the emergency room with hemoptysis consisting of relevant amounts of fresh blood. She was treated with phenprocoumon for 11 years following mechanical aortic valve replacement without any complication. Laboratory results revealed phenprocoumon over dosage with international normalized ratio over 6. Chest radiograph showed diffuse alveolar infiltrates conformable to diffuse alveolar hemorrhage. Besides the pulmonary complication no other bleeding occurred. She needed noninvasive ventilatory support for 24 h to cope with the symptoms of an acute respiratory failure. After substitution of vitamin K dependent blood clot factors resulting in a normalized coagulation hemoptysis which persisted for another 3 days followed by a slow recovery. Other causes of diffuse alveolar hemorrhage were excluded in our patient. This case report presents a rare case with diffuse alveolar hemorrhage as the leading and sole symptom due to phenprocoumon overdose.

A systematic review and survey of the management of unexpected neonatal alloimmune thrombocytopenia.

BACKGROUND: Unexpected neonatal alloimmune thrombocytopenia (NAIT) may have devastating consequences and its management is challenging. To design future trials, evidence from the literature and existing best practice need review. STUDY DESIGN AND METHODS: This study was a cross-sectional survey of neonatal units in Germany and Canada to determine management strategies of NAIT and a systematic search for randomized controlled trials (RCTs). RESULTS: Management of NAIT differs substantially between countries with regard to platelet (PLT) thresholds for screening, initiation of therapy, and treatment. Seventy-seven percent of Canadian physicians versus 68 percent of German physicians screen preterm and term infants, at a PLT threshold of 30 x 10(9) to 100 x 10(9) per L. In preterm infants, 60 percent of Canadian neonatologists commence treatment at a PLT count of between 30 x 10(9) and 50 x 10(9) per L. In Germany 32 percent of the physicians start treatment at this level and 25 percent use a threshold of between 10 x 10(9) and 20 x 10(9) per L. In term infants, 6 percent of the Canadian physicians and 16 percent of the German physicians use even lower treatment triggers of between 5 x 10(9) and 10 x 10(9) per L. In the presence of bleeding, 61 percent of German physicians await the arrival of antigen-negative PLTs, while 64 percent of Canadian neonatologists prefer intravenous immunoglobulin or random-donor PLTs (81%). Maternal PLTs are utilized by 31 percent of physicians in both countries. No RCTs were identified. CONCLUSION: In the absence of RCTs, management of unexpected NAIT differs between countries. Clinicians and transfusion services may use the results of our study to develop collaborative protocols, redefine preferred hospitalwide strategies, and design future controlled trials.

Benefit and risk of heparin for maintaining peripheral venous catheters in neonates: a placebo-controlled trial.

OBJECTIVES: Heparin addition to infusion fluids is used to prolong catheter patency in newborns. Heparin may also induce adverse effects such as bleeding complications and immune-mediated heparin-induced thrombocytopenia (HIT). One objective was peripheral venous catheter patency with heparinization of continuous infusions (0.5 IU/mL). Secondary objectives were incidences of bleeding, clinically manifest HIT, HIT antibodies, and catheter-related complications. STUDY DESIGN: Inclusion criteria were anticipated need for intravenous peripheral infusion (>or=5 days for HIT-related endpoints) and postnatal age <28 days at study entry. Exclusion criteria were bodyweight <1000 g, congenital malformation, need for therapeutic anticoagulation or mechanical ventilation, and severe bleeding. HIT antibodies were assessed by enzyme-linked immunosorbent assay. RESULTS: A total of 145 infants received heparin, and 151 infants received saline. Patient characteristics, number of additional drugs, duration of treatment, and location and size of catheters did not differ. Patency of catheters was 7.4 hours longer in the heparin group (33.8 hours vs 26.4 hours, P<.0001), but the total numbers of catheters did not differ (565 vs 692, P=.3). No infant developed HIT antibodies. Incidences of bleeding complications and thrombocytopenia were comparable between groups. CONCLUSIONS: Balancing the benefits against the risks of heparin addition and the rare complication of HIT, we will not use 0.5 IU/mL heparin addition to parenteral fluids.