Angela Treml

Massive Transfusion Protocols: A Survey of Academic Medical Centers in the United States.

BACKGROUND: Massive transfusion protocols (MTPs) have been adopted in many hospitals, and they may improve outcomes, as well as decrease the number of blood products transfused. However, there are no specific guidelines regarding the number and types of products that should be included in these protocols. MTPs may vary from hospital to hospital. METHODS: A short, web-based survey was sent to blood bank medical directors at academic institutions to learn details about MTPs. RESULTS: A total of 107 survey requests were sent, and 56 were completed (52% response rate). All who responded had an MTP in place. Nearly all (n = 55, 98.2% [95% CI, 90.6%–99.7%]) base their protocol on delivery of fixed amounts and ratios of blood products, with only a minority incorporating any elements of laboratory-directed therapy. The most common target, red blood cell (RBC):plasma ratio, is 1:1 (n = 39, 69.9% [95% CI, 56.7%–80.1%] of respondents). The majority (n = 36, 64.3% [95% CI, 51.2%–75.6%]) provide 6 or more units of red blood cells in the first MTP packet. CONCLUSIONS: One-hundred percent of survey respondents had an MTP in place. Despite a lack of published guidelines regarding MTPs, the survey results demonstrated substantial uniformity in numbers of products and target transfusion ratios.

Red blood cell alloimmunization: lessons from sickle cell disease

R ed blood cell (RBC) transfusion is a lifesaving therapy for patients with chronic anemias, including sickle cell disease and myelodysplastic syndrome. However, with multiple intermittent or chronic monthly transfusions, the concern for RBC alloimmunization arises. This issue of TRANSFUSION includes two articles that discuss specific patient groups at increased risk of alloimmunization compared to the general population and most patient groups as well. Although difficult to accurately determine, the baseline incidence of alloimmunization in the general population has been estimated to be approximately 0.5% to 1.5%. Some studies have found a higher rate of alloimmunization among hospital patients, but often these studies include clinically insignificant or naturally occurring antibodies. Of note, Redman and colleagues performed a prospective study of posttransfusion patients who had received a mean of 3 RBC units and they surprisingly found that 8.4% of those patients developed RBC alloantibodies; this higher than expected rate of alloimmunization may be related to their prospective study design or their sensitive serologic methods, which included enzyme or polybrene techniques in addition to indirect antiglobulin tests. In contrast, the incidence of RBC alloantibody formation in patients with sickle cell disease is significantly higher. Before the introduction of prophylactic phenotypic matching, the alloimmunization rate among patients with sickle cell disease ranged from 8% to 36% depending on the study and the specific patient population. A review of 12 publications found a mean rate of 25%. The risks of alloimmunization in this multiply transfused population are real. With the development of alloantibodies, the patient’s serologic evaluation may become complex and lead to difficulty obtaining compatible units, resulting in potentially critical delays in blood availability for emergent transfusions. Additionally, alloimmunization is associated with an increased risk of acute and delayed hemolytic transfusion reactions that may be complicated by hyperhemolysis, a life-threatening complication of transfusion which is seen predominantly in patients with sickle cell disease. The high rate of alloimmunization in patients with sickle cell disease is likely multifactorial. A significant contributory factor is the racial discordance between donor and recipient. The majority of blood donors in the United States are white, while most patients with sickle cell disease are of African descent. This racial discordance results in a disparity in RBC antigen distributions between donors and patients. However, there are other contributory factors, as somewhat higher alloimmunization rates are even seen when the donor and recipient are ethnically similar. Of note, a study by Natukunda and colleagues found that 6.1% of Ugandan patients with sickle cell disease were alloimmunized despite low transfusion exposure and racial homogeneity between donors and recipients. Other influencing factors may include the immune responsiveness of the patient, the number of transfusion exposures, and the patient’s age at first transfusion. Efforts to prevent alloimmunization in patients with sickle cell disease have focused on prophylactic antigen matching. Several studies have advocated prophylactic matching for C, E, and K antigens for patients with sickle cell disease, whereas some groups use extended phenotypic matching. These antigen-matching protocols have been associated with a reduction in the rate of alloimmunization and a decrease in hemolytic transfusion reactions. Despite this reported success, studies and surveys have demonstrated no consistent standard of care with significant variability in transfusion practice particularly related to the extent of antigen matching for these patients. In a survey of 1182 North American laboratories, Osby and Shulman found that the majority of laboratories only matched for ABO and D in nonalloimmunized patients with sickle cell disease. One-third of laboratories provided RBCs that were prophylatically matched for C, E, and K antigens and one-seventh of the laboratories provided units matched for Jk, Jk, Fy, and Fy antigens. Afenyi-Annan and coworkers surveyed the transfusion management practices at the participating institutions within the NIH Comprehensive Sickle Cell Centers. Within this focused group of predominantly academic institutions, variability of transfusion practice persists. These institutions showed more consensus regarding matching for Rh and Kell antigens, but differences in matching for additional antigens remained. Some experts do not recommend prophylactic matching for nonalloimmunized patients with sickle cell disease, because the majority of patients do not make antibodies and the provision of phenotypically matched RBCs is costly and may delay care depending upon the extent of prophylactic matching. They would argue that when patients initially become alloimmunized, most typically develop a single alloantibody that may be associated with a clinically benign delayed serologic transfusion reaction or a mild delayed hemolytic transfusion TRANSFUSION 2013;53:692-695.

Cancer-related microangiopathic hemolytic anemia.

A 63-year-old man with a history of urothelial carcinoma status postnephrourectomy in 2011 presented with fatigue, chest discomfort, and dyspnea on exertion to an outside hospital in 2015. He was found to be anemic and thrombocytopenic. Further workup demonstrated schistocytes on peripheral blood smear (see figure, a), decreased haptoglobin, increased bilirubin, elevated lactate dehydrogenase, and normal PT/INR. Fibrinogen and PTT were not drawn at the time. Thrombotic thrombocytopenic purpura (TTP) was suspected. Therapeutic plasma exchange (TPE) was initiated, and the patient was then transferred to our hospital for further management. After nine TPE procedures, there was no clinical response. ADAMTS13 activity was ordered, but unfortunately not drawn until after the first TPE. The value was within normal range. Due to history of carcinoma, a PET-CT was done which demonstrated an abnormal enhancement in the spine. A targeted biopsy revealed marrow involvement by adenocarcinoma with signet ring differentiation (see figure, b). Cancer-related microangiopathic hemolytic anemia (CA-MAHA) may mimic TTP. Malignancies most commonly associated with MAHA include gastric, breast, and lung carcinomas. Compared with TTP, CA-MAHA patients often are older and present with gradual onset weight loss, localized pain, respiratory symptoms, and leukoerythroblastic reaction on peripheral blood smear and do not respond to TPE. Before the initiation of TPE, it is important to consider other causes of MAHA and, if TTP is suspected, to measure ADAMTS13 activity before starting TPE. Failure to recognize other causes of MAHA may expose patients to unnecessary treatment and risks associated with TPE and delay appropriate treatment.

The management of anticoagulation in patients undergoing therapeutic plasma exchange: A concise review

We surveyed multiple apheresis centers represented by the authors for their clinical approach to the management of anticoagulation issues during therapeutic plasma exchange (TPE). We present the results of their practices and a review of the pertinent literature. As plasma is removed during TPE, replacement with all or partial non‐plasma‐containing fluids (eg, 5% albumin) may lead to significant changes in hemostasis. These changes are amplified in patients who are receiving anticoagulation. We discuss various anticoagulants as well as the monitoring and adjustment of anticoagulation before, during, and after TPE. No single guideline can be applied, but rather, patients must be monitored individually, taking into account their often complex clinical conditions and medication profiles.

Therapeutic plasma exchange as part of multimodal treatment of acquired hemophilia in a patient with concurrent acute intracerebral bleed and pulmonary embolism

Autoantibodies against Factor VIII (FVIII) define the rare but life‐threatening bleeding disorder acquired hemophilia A (AHA). Correction of FVIII deficiency and eradication of the factor inhibitor are the ultimate therapeutic goals in this disorder. Bypassing agents such as recombinant factor VIIa (rFVIIa) or FVIII inhibitor bypassing agent are often used to control coagulopathy before the inhibitor is eradicated. Bypassing agents carry a risk of thrombosis, however.

Red blood cell exchange in patients with sickle cell disease-indications and management: a review and consensus report by the therapeutic apheresis subsection of the AABB: RBC EXCHANGE

A prior practice survey revealed variations in the management of patients with sickle cell disease (SCD) and stressed the need for comprehensive guidelines. Here we discuss: 1) common indications for red blood cell exchange (RCE), 2) options for access, 3) how to prepare the red blood cells (RBCs) to be used for RCE, 4) target hemoglobin (Hb) and/or hematocrit (Hct) and HbS level, 5) RBC depletion/RCE, and 6) some complications that may ensue.

What is the evidence to support the use of plasma exchange as first‐line therapy for N‐methyl d‐aspartate receptor antibody encephalitis?

The recently published seventh edition of the “Guidelines on the Use of Therapeutic Apheresis in Clinical Practice” outlines the available evidence supporting and refuting the use of therapeutic apheresis as a medical treatment. The authors are to be congratulated for their important contribution to the medical literature, which helps to ensure that peer-reviewed medical literature is used to guide the care of patients who are being evaluated as possible apheresis candidates. Now that the seventh edition of these guidelines has been available for several months, most apheresis practitioners have had an opportunity to begin to appreciate how the current recommendations vary from previous iterations. One key difference is the new, category I classification for the use of therapeutic plasma exchange (TPE) as a treatment for N-methyl D-aspartate receptor encephalitis (NMDAr). In the sixth edition, NMDAr was grouped with other paraneoplastic neurological syndromes (eg, paraneoplastic cerebellar degeneration, etc.), which were collectively assigned a category III rating. The technical notes of the sixth edition of the guidelines even contained an unusual caveat to the use of TPE for these indications, “TPE cannot be considered standard therapy for autoimmune paraneoplastic neurologic syndromes.” The fifth edition (published in 2010) does not mention NMDAr. Given the rareness of the diagnosis of NMDAr, and the lack of any published clinical trials over this time period, we were surprised at the rapidly shifting recommendations for this indication. Recurring themes in the treatment of NMDAr include early treatment, tumor removal (if present), and the recognition that patients without tumors are more likely to require second-line treatment with cyclophosphamide or rituximab. The medical literature provides only very limited assessments as to whether patient outcomes are even improved when TPE is pursued as a first-line treatment. As a reflection of the lack of published evidence, the authors of the Guidelines have assigned a 1C grade to the recommendation, which reflects that the evidence to support TPE in this setting is of low or very low quality. This, in conjunction with the fact that fewer than half of patients seem to actually undergo TPE, and virtually all patients who are treated with TPE are simultaneously treated with steroids, makes it difficult to understand the “strong” recommendation for TPE to be used as “first line” therapy for NMDAr.4–6 One report explicitly recommends against TPE due to the increased risks of adverse outcomes in patients with autonomic instability. Therefore, the role of TPE as a treatment for NMDAr appears to require further study and carefully planned individual treatment schemas. At present, the decision to include TPE as a treatment modality should depend on patient-specific factors, such as age, presence of tumor, nature of symptoms, risk of infection, and the degree of autonomic instability. In light of this, we feel that a category III classification continues to be appropriate. While the Guidelines makes the point that the low grade of evidence can be used to “soften” a category I classification, in our collective experience, a category I classification is widely interpreted by the medical community to mean that apheresis-based treatment is an effective treatment that represents the standard of care. Admittedly, this is an unintended consequence of the Guidelines, but it nonetheless has important implications for the management of these patients. For example, facilities without TPE may feel compelled to transfer these patients to centers that offer apheresis. In addition, in some cases, treatment with second-line immunotherapy such as cyclophosphamide and rituximab may be unnecessarily delayed while a weekslong therapeutic trial of apheresis is completed. We are also aware of at least one instance where unjustified enthusiasm regarding the efficacy of TPE led to hesitation to perform definitive surgery.

Acquired factor XI deficiency and therapeutic plasma exchange

Congenital factor XI (FXI) deficiency is associated with a variable bleeding phenotype. Recent reports have documented the use of therapeutic plasma exchange to rapidly and isovolumetrically increase FXI levels before invasive procedures in patients with congenital FXI deficiency.

Daratumumab and Red Cell Serologic Testing: A Single-Institution Experience

Next-generation sequencing (NGS) is a robust method to assess clinically relevant gene mutations in tumor specimens; however, this technology requires higher minimum DNA inputs for successful analysis than other molecular techniques. Simultaneously, smaller radiologic targets and image-guided brushing/biopsy techniques lead to smaller sample volumes, while competing ancillary procedures such as rapid onsite evaluation or immunohistochemistry may deplete the amount of tumor available for testing. Delay or cancellation of molecular testing related to inadequate DNA is observed in 10% of processed samples in our lab. To minimize this impact, we examined the use of stained cytology samples for molecular testing. Autopsy tissue was used to create essentially identical cytologic preparations stained with Diff-Quik, Papanicolaou, and H&E to be compared to both fresh and formalin-fixed paraffin-embedded (FFPE) tissue. Several organs representing the spectrum of cellularity were sampled from each autopsy (lung, liver, spleen, and thyroid). Two cases with tumor tissue were evaluated in addition to these normal tissue types. Aperio image scanning was utilized to simulate archiving of slides and test the correlation of automated cell counting with the DNA quantity obtained. Coverslips were removed with xylene, imprints were scraped, and DNA extracted using the QIAamp DNA FFPE kit. DNA yield was measured using fluorometry (Qubit), and the AJCP / MEETING ABSTRACTS