Janice G. McFarland

Toward an understanding of transfusion‐related acute lung injury: statement of a consensus panel

From Kleinman Biomedical Research, Victoria, British Columbia, Canada; the University of British Columbia, Vancouver, British Columbia, Canada; the University of Alberta, Edmonton, Alberta, Canada; Toronto, Ontario, Canada; the University of Michigan, Ann Arbor, Michigan; The Blood Center of Southeastern Wisconsin, Milwaukee, Wisconsin; Elora, Ontario; Canada; McMaster University, Hamilton, Ontario, Canada; the Royal Columbian Hospital, New Westminster, British Columbia, Canada; Halifax, Nova Scotia, Canada; the Quebec Public Health Institute, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada; and the University of Toronto, Toronto, Ontario, Canada. Address reprint requests to: Morris Blajchman, MD, Depts. of Pathology and Medicine, McMaster University, 1200 Main St., West, HSC 2N34, Hamilton, Ontario, Canada L8N 3ZS; e-mail: blajchma@mcmaster.ca. Dr Meade is a Peter Lougheed Scholar of the Canadian Institutes of Health Research. This Consensus Conference was funded by Canadian Blood Services and Hema-Quebec, with additional support from the International Society of Blood Transfusion’s Biomedical Excellence for Safer Transfusion (BEST) subcommittee. Received for publication August 22, 2004; revision received August 26, 2004, and accepted August 26, 2004. TRANSFUSION 2004;44:1774-1789. R E V I E W

Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage

BACKGROUND We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia. METHODS We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria). RESULTS In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001). CONCLUSIONS Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.)

Antenatal treatment of neonatal alloimmune thrombocytopenia.

Neonatal alloimmune thrombocytopenia results from the formation of a maternal antibody to a paternal antigen on fetal platelets. Intracranial hemorrhage, which may be antenatal, occurs in approximately 15 to 20 percent of infants with this form of thrombocytopenia. In families with an affected infant, 75 percent of subsequent infants are affected. We report the results of antenatal treatment with intravenous gamma globulin, with or without dexamethasone, in seven pregnant women who had previously had infants who had severe alloimmune thrombocytopenia. The platelet count increased by a mean (+/- SD) of 72.5 +/- 62 x 10(9) per liter in the six fetuses in whom periumbilical blood sampling was performed. All seven treated fetuses had platelet counts above 30 x 10(9) at birth, and none had an intracranial hemorrhage, in contrast to all seven of their respective untreated siblings, who had lower platelet counts and three of whom had intracranial hemorrhages (antenatal in two infants). Mild intrauterine growth retardation was observed in one treated infant; all seven infants have developed normally in the two months to four years since birth. We conclude that intravenous gamma globulin, with or without dexamethasone, is effective in elevating the fetal platelet count in severe cases of neonatal alloimmune thrombocytopenia and in helping to avoid intracranial hemorrhage.

Effects of Red-Cell Storage Duration on Patients Undergoing Cardiac Surgery

BACKGROUND Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoing cardiac surgery may be especially vulnerable to the adverse effects of transfusion. METHODS We conducted a randomized trial at multiple sites from 2010 to 2014. Participants 12 years of age or older who were undergoing complex cardiac surgery and were likely to undergo transfusion of red cells were randomly assigned to receive leukocyte-reduced red cells stored for 10 days or less (shorter-term storage group) or for 21 days or more (longer-term storage group) for all intraoperative and postoperative transfusions. The primary outcome was the change in Multiple Organ Dysfunction Score (MODS; range, 0 to 24, with higher scores indicating more severe organ dysfunction) from the preoperative score to the highest composite score through day 7 or the time of death or discharge. RESULTS The median storage time of red-cell units provided to the 1098 participants who received red-cell transfusion was 7 days in the shorter-term storage group and 28 days in the longer-term storage group. The mean change in MODS was an increase of 8.5 and 8.7 points, respectively (95% confidence interval for the difference, -0.6 to 0.3; P=0.44). The 7-day mortality was 2.8% in the shorter-term storage group and 2.0% in the longer-term storage group (P=0.43); 28-day mortality was 4.4% and 5.3%, respectively (P=0.57). Adverse events did not differ significantly between groups except that hyperbilirubinemia was more common in the longer-term storage group. CONCLUSIONS The duration of red-cell storage was not associated with significant differences in the change in MODS. We did not find that the transfusion of red cells stored for 10 days or less was superior to the transfusion of red cells stored for 21 days or more among patients 12 years of age or older who were undergoing complex cardiac surgery. (Funded by the National Heart, Lung, and Blood Institute; RECESS ClinicalTrials.gov number, NCT00991341.).

TRALI due to granulocyte‐agglutinating human neutrophil antigen‐3a (5b) alloantibodies in donor plasma: a report of 2 fatalities

BACKGROUND : TRALI is usually an immunologic reaction to WBC antibodies in infused plasma and ranks second only to ABO mismatch as a cause of transfusion‐associated death. Implicated donors are usually multiparous women (≥3 pregnancies).

Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management.

Summary.  Drug‐induced immune thrombocytopenia (DITP) can be triggered by a wide range of medications. Although many cases of DITP are mild, some are characterized by life‐threatening bleeding symptoms. The pathogenesis of DITP is complex, in that at least six different mechanisms have been proposed by which drug‐induced antibodies can promote platelet destruction. It is possible in many cases to identify antibodies that react with platelets in the presence of the sensitizing drug, but the required testing is technically demanding and not widely available. Therefore, a decision on whether to discontinue an implicated medication in a patient suspected of having DITP must be made on clinical grounds. An algorithm is available that can be helpful in assessing the likelihood that a particular drug caused thrombocytopenia, but the most important aspects of patient management are a high index of suspicion and a careful history of drug exposure in an individual who presents with acute, often severe thrombocytopenia of unknown etiology. How drugs induce platelet‐reactive antibodies and how, once formed, the antibodies cause platelet destruction following exposure to the drug is poorly understood. Further studies to address these issues and characterize more completely the range of drugs and drug metabolites that can cause DITP are needed.

Rapid determination of platelet alloantigen genotypes by polymerase chain reaction using allele-specific primers

BACKGROUND: The technique of allele‐specific polymerase chain reaction (PCR) amplification has been adapted for DNA‐based human platelet alloantigen typing.

Clinical and diagnostic comparison of neonatal alloimmune thrombocytopenia to non-immune cases of thrombocytopenia.

Affected patients with neonatal alloimmune thrombocytopenia (AIT) are often severely thrombocytopenic and, if so, may suffer an intracranial hemorrhage (ICH). This study was undertaken to compare the outcome of cases of AIT to cases of neonatal thrombocytopenia shown not to be AIT and to identify clinical features that would facilitate the diagnosis.

Parallel randomized trials of risk-based therapy for fetal alloimmune thrombocytopenia.

OBJECTIVE: Antenatal therapy with intravenous immunoglobulin (IVIG) and prednisone has been shown to improve fetal thrombocytopenia and reduce the incidence of intracranial hemorrhage in neonatal alloimmune thrombocytopenia. Optimization of this therapy for individual patients, however, has yet to be achieved. METHODS: In these parallel, randomized, multicenter studies, 78 patients in 79 pregnancies were stratified to 2 different treatment arms based on the presence of a peripartum intracranial hemorrhage in a previously affected sibling and/or the initial fetal platelet count. Patients with a history of an antenatal intracranial hemorrhage in a prior pregnancy were excluded. RESULTS: Forty women whose children from a previous birth had a peripartum intracranial hemorrhage or whose current fetus had an initial platelet count less than 20,000/mL3 were randomly assigned to receive IVIG plus prednisone or IVIG alone. The mean increase in fetal platelet counts in the following 3 to 8 weeks was 67,100/mL3 and 17,300/mL3, respectively (P < .001). Thirty-nine patients whose prior affected child did not have an intracranial hemorrhage and whose initial platelet count was more than 20,000/mL3 were randomly assigned to receive IVIG alone or prednisone alone. There were no significant differences, and 33 (85%) had birth platelet counts more than 50,000/mL3. There were 11 (6%) significant complications after a total of 175 fetal blood sampling procedures, 2 of which led to fetal or neonatal deaths. CONCLUSION: The spectrum of disease severity of alloimmune thrombocytopenia is reflected in the initial fetal platelet count and response to therapy. Fetal blood sampling may be associated with significant fetal/neonatal morbidity and mortality. Empiric therapy sufficient to treat the most severely affected fetuses will overtreat others and is likely to be associated with additional maternal morbidity.

Mechanisms of transfusion-related acute lung injury (TRALI): anti-leukocyte antibodies.

There is abundant evidence that leukocyte antibodies in blood donor products are somehow involved in transfusion-related acute lung injury (TRALI). Human leukocyte antigen (HLA) class I, HLA class II, and neutrophil-specific antibodies in the plasma of both blood donors and recipients have been implicated in the pathogenesis of TRALI. The case for a relationship between leukocyte antibodies and TRALI is more compelling if concordance between the antigen specificity of the leukocyte antibodies in the donor plasma and the corresponding antigen on the cells of the affected recipient is demonstrated. Such antibody-antigen concordance can be investigated by typing the recipient for the cognate leukocyte antigens or by cross-matching the donor plasma against the recipients leukocytes. Two proposed pathophysiologic mechanisms for TRALI have received the most attention: the antibody hypothesis and the two-event hypothesis. The final common pathway in all of the proposed pathogenic mechanisms of TRALI is increased pulmonary capillary permeability, which results in movement of plasma into the alveolar space causing pulmonary edema. A typical TRALI serologic workup consists of tests for HLA class I and II and neutrophil-specific antibodies. The use of flow cytometry and HLA-coated microbeads is recommended for detection of HLA antibodies in plasma of implicated blood donors and a combination of the granulocyte agglutination test and granulocyte immunofluorescence test for detection of neutrophil-specific antibodies. Genotyping for class I and II HLA and for a limited number of neutrophil antigens may also be helpful in establishing antibody-antigen concordance.