The Daily Sign-Out

"Transfusion News" a new site launched by AABB and Ortho Clinical Diagnostics

Check out this new web site for transfusion-related news. Excellent site design and content.

AABB has partnered with Ortho Clinical Diagnostics to launch Transfusion News, a website that features videos, articles, breaking news and commentary from transfusion experts. Transfusion News will provide video updates on the 15th and 30th of each month, featuring important information about blood banking, transfusion medicine, tissue transplantation, blood policies, hematopoietic stem cells, cellular therapies and related fields. Transfusion News may be accessed through the website for the journal Transfusion, under "special features."

Source: AABB Weekly Report e-newsletter, August 3, 2012

Circulating factor identified for focal segmental glomerulosclerosis

So I have been serving as the therapeutic apheresis physician for my colleague (and mentor) Dr. Bruce McLeod (editor of Apheresis: Principles and Practice).  Big shoes to fill.

One of our regular patients for plasmapheresis has the diagnosis of focal segmental glomerulosclerosis (FSGS).  It has always interested me how we can best follow apheresis patients for therapeutic response.  Therefore, it was with great interest that I stumbled on a recent article by Wei et al. published in the August 2011 issue of Nature Medicine in which they identify a circulating permeability factor associated with the development of FSGS in humans and mice: suPAR (soluble urokinase receptor).

FSGS, the most common histologic injury seen in adults with nephrotic syndrome in the U.S., is understood to be caused by podocyte injury.  Mutations in several proteins known to be crucial in podocyte structure and/or function have been identified that are associated with FSGS.  It has long been suspected that the cause of the vast majority of FSGS cases are due to some circulating factor based on the clinical observations that FSGS can occur immediately after transplant or as a de novo disease in transplanted kidneys--but the identification of this factor has been frustratingly elusive.

Podocyte urokinase receptor (uPAR; encoded by PLAUR) is a GPI-anchored membrane recpetor protein that is a receptor for urokinase but also interacts with a variety of other transmembrane receptors, including integrins.  uPAR can be released  from  the plasma membrane  as  a  soluble molecule  (suPAR)  by  cleavage  of  the  GPI anchor.  The authors have recently reported that induced uPAR expression in podocytes can cause podocyte foot process effacement and proteinuria, and so they hypothesized that suPAR might be a candidate circulating factor in FSGS.

Wei et al. have shown that elevated levels of suPAR were present in the plasma of two-thirds of the 78 patients with FSGS that they studied.  Further, they found the highest suPAR levels in pretransplant sera from patients with FSGS who later developed FSGS after transplantation.  They also found that lowering the levels of suPAR by plasmapheresis led to disease remission.

The paper also sheds light on the pathogenesis of FSGS.  Their previous work showed that uPAR is required for activation of beta-3 integrin signaling within the kidney podocyte.  In this paper, they demonstrate that suPAR also binds and activates this protein.  Increased podocyte beta-3 integrin signaling leads to accelerated podocyte foot process changes that result in effacement, proteinuria, and initiation of FSGS.

A key question is what the source is for increased suPAR.  The authors suggest that neutrophils and monocytes may be responsible.  This work is an important advance for understanding an enigmatic disease and I highly recommend taking the time to read this as my summary really doesn't do it justice.  One can easily envision an ELISA for testing and monitoring people suspected of or having FSGS.  But before using suPAR as a diagnostic test or as a way to monitor therapeutic plasmapheresis, further work must be done to validate diagnostic "levels" and correlate falling levels to plasma exchanges.

Henry VIII, the Kell blood group system and the McLeod syndrome

ScienceDaily (Mar. 3, 2011) — Blood group incompatibility between Henry VIII and his wives could have driven the Tudor king's reproductive woes, and a genetic condition related to his suspected blood group could also explain Henry's dramatic mid-life transformation into a physically and mentally-impaired tyrant who executed two of his wives.

http://www.sciencedaily.com/releases/2011/03/110303153114.htm#

Fascinating medical history article!  The Kell blood group system is probably the third most important blood group system (after ABO and Rh) because Kell antigens are highly immunogenic and Kell antibodies can cause hemolytic transfusion reactions and hemolytic disease of newborn.  Fortunately, only about 9% of whites and 2% of blacks are K positive; so although K antibodies are relatively common, it is also relatively easy to obtain K-negative blood for transfusion.

The Kell antigens are carried by a red cell membrane glycoprotein with a large globular extracellular C-terminal component.  The Kell protein interacts with the RBC surface membrane with a 37 kD protein XK (Kx antigen) which plays a key role in the expression of Kell antigens.  Interestingly, the gene encoding XK is located on the petite arm of the X chromosome and is near the foci for X-linked chronic granulomatous disease (CGD) and Duchenne muscular dystrophy (DMD).

The McLeod phenotype is a rare but clinically interesting variant in the Kell blood group system.  Individuals with this phenotype lack the Kx antigen and thus express reduced levels of Kell antigens.  This phenotype is associated with acatholytic RBC morphology and low-grade chronic hemolytic anemia.  Neuromuscular symptoms, as discussed in the article above with respect to good ol' 'enry, are frequently reported in patients with McLeod syndrome and may be related to lack of Kx expression.  Finally, the McLeod phenotype is associated with other rare syndromes, most frequently (as one might expect) with CGD and DMD or Becker muscular dystrophy.

NHLBI to fund research into storage lesion in donated blood

This is a bit "old news" but worth relaying.  In late June, the National Heart, Lung and Blood Institute announced the funding of nine grants to explore the effect of storage time on donated blood.  This is timely given recent studies that suggest increased risk of adverse cardiovascular and other organ events in people who received blood transfusions in which the storage time was greater than two weeks.

Current FDA guidelines permit liquid RBCs to be stored for up to 42 days (longer if the blood is frozen)--but the average unit of RBCs is transfused after 16 days' storage.  We at my institution consider an outdated RBC product (which is thus wasted) to be an exceptional event and call for a "root cause analysis" when this occurs--which fortunately is extremely rare.  (Plateletpheresis products are a different story for different reasons.)  Blood banks and transfusion services are between Scylla and Charybdis here: there is a chronic shortage of donated blood in the U.S. so any shortening of acceptable storage life would further exacerbate that shortage BUT there is the critical imperative to provide safe blood.

THe storage lesion in banked blood refers to the metabolic changes that occur in the RBCs during storage as well as the effects of hemolysis and shortened RBC survival with storage.  This results in the formation of RBC microparticles, release of free hemoglobin, and loss of RBC enzymatic functions--which not results in an ineffective or suboptimal therapeutic effect of the transfusion but also can cause widespread systemic deleterious effects.

These will be the first research projects to systematically examine collection, preparation, and storage practices as they relate to the RBC storage lesion.

Prevalence of HHV-8 in U.S. blood donors is low

One less thing to worry less about regarding transfusion-transmitted infections.

 

Transfusion: Prevalence of human herpesvirus 8 in healthy blood donors is low.

The first systematic study of human herpesvirus 8 in U.S. blood donors found that the prevalence of detectable genomes of HHV-8, which causes Kaposi's sarcoma, is very low in healthy donors. According to the study, featured in the May issue of Transfusion, a sensitive and quantitative real-time polymerase chain reaction assay was used to detect HHV-8 DNA from purified CD19+ B lymphocytes from 962 randomly selected U.S. whole-blood donors.

Read the abstract and editorial.

Pathologist Consults for Transfusion Issues

Over the years, I have developed a list of situations for a hospital transfusion service for which I (or the on-call pathologist) should be notified and consult with the med tech in the "blood bank."  Some of them are indeed mandatory but all of them generally are what I would described as deviations from the normal SOP.  I use my judgment on whether or not to directly call clinicians, the O.R., or go up to the floor--but when I have done any of the aforementioned, my input and advice has always been well-received.  Most of these are not emergency situations and encourage the techs to call us when it is practical even if it is in the middle of the night.  From a practical standpoint, I have learned that communication the next morning or day is by someone who was not actually involved in the situation and is handing off a scribbled note or incomplete verbal communication.  We (as pathologists) shouldn't underestimate our impact into patient care in unusual transfusion situations.

• Request for emergency release of uncrossmatched RBCs.  Although the blood needs to be out the door before I am reached, I want to know about this as soon as possible so I can speak to the clinicians and give them some reassurance and timeframes as more appropriate units are available (ABO- and then crossmatch-compatible).
• Adverse reactions to transfusion.  This is one of those mandatory situations and one in which we always issue a written report or note.  Also includes suspected transfusion-related acute lung injury (TRALI) and transfusion-transmitted infections (e.g., "look-back" and subsequent donor testing).
• High utilization of blood components.  This is the massive transfusion situation.  The anesthesiologists are fairly well-aware of the physiological sequelae of massive transfusion, so I mainly call them to get an idea of how the patient is doing so I can communicate to the blood bank on how many more units may be needed, our inventory, switching blood types, and whether or not an emergency run is needed to replenish our supply.
• Requests for specialized blood components.  This incorporates requests for washed RBCs, CMV-seronegative components, etc.  It is amazing how often such requests are made "because that is what we did in residency."  Most of these are not necessary and it provides me a "teaching moment."
• Feto-maternal hemorrhage.  The blood bank techs interpret the Kleihauer-Betke stain for the purpose of determining the appropriate dose of RhoGam and are not comfortable doing this.  We score adequately on proficiency testing but I think it touches the patient too much for them.  Anyway, I just like to know about these situations.
• Serological problems.  This includes positive DATs, newly discovered alloantibodies and autoantibodies, ABO discrepancies, etc.  This constitutes most of the day-to-day consults and mostly consists of reviewing the work-up.  I also approve send-outs to the Red Cross for additional work-ups and sign-off on the reports as they come back.  I just like knowing about these too and occasionally talking to clinicians if the work-up is delaying a patient receiving blood.
• Possibly inappropriate utilization of blood components.  This may be an emerging area for consultation but will likely be at a higher order level rather than at the direct patient care level.  Techs don't like functioning as gatekeepers and telling surgeons "no" so I encourage them to call me if something doesn't smell or sound right.

Hope you find this of help.  Your comments and questions are welcome.  Are there situations that you confront where a pathologist consultation is helpful?

Study opens discussion on use of plasma from female donors

Study opens discussion on use of plasma from female donors - Related Stories - AABB SmartBrief.

Noted this from my daily AABB SmartBrief.  Transfusion-related acute lung injury (TRALI) has been a stubbornly enigmatic disease entity since being first described in detail about 25 years ago.  Since antibody-associated TRALI (the most common and severe form) has almost exclusively been associated with women donors with a history of pregnancy, many centers have followed a straight-forward policy of excluding all female donors for plasma-rich products (e.g., FFP and apheresis platelets).  The U.K. instituted this policy nationally in 2003.  While in that country saw a decline of 66% in the incidence of "probable" TRALI and associated deaths in the three years following adoption of this policy, the price is exclusion of a large pool of donors.  Further refinements of such a policy are in progress but perhaps this study might provoke a prospective study to be undertaken.

FDA reports fatalities related to transfusion and blood collection for 2009

The FDA has released the summary for 2009 of transfused-related fatalities.  Of 74 transfusion-recipient fatality reports, they determined that 44 of the fatalities were transfusion-related, 22 of the fatalities were cases in which transfusion could not be ruled out as the cause of the fatality, and 8 of the fatalities were unrelated to the transfusion.

Interestingly, transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) accounted for the highest numbers of reported fatalities, followed by non-ABO hemolytic transfusion reactions. 

Another finding of note is that there were no reports of fatal microbial infections associated with RBCs, compared to 5 reports in FY2008, which were all due to Babesia infections.

A pdf of the report can be downloaded at the link above.

Dose of platelets in prophylactic transfusions for severe thrombocytopenia

Slichter and colleagues published a multi-institutional randomized trial in the February 18 issue of New England Journal of Medicine (article abstract) that evaluates the effect of platelet dose on various transfusion and clinical outcomes in patients receiving prophylactic transfusions for severe hypoproliferative thrombocytopenia.

The study included 1272 hospitalized patients who underwent allogeneic or autologous hematopoietic stem cell transplant (HSCT) or chemotherapy for hematologic or solid malignancies who were expected to have platelet counts of 10,000/mm3 or less for 5 or more days and received at least 1 plt transfusion--and excluded patients with active bleeding grade 2 or higher and those refractory to platelet transfusions (amongst other things).  Patients were randomly assigned to received platelet transfusions of low-dose (1.1x10e11), medium-dose (2.2x10e11)(=standard adult dose), and high-dose (4.4x10e11).  The primary end point was grade 2 or higher bleeding (according to the WHO bleeding scale).

Take-it-home: There was no significant difference in rates of grade 2 or higher bleeding or of other adverse events.

A couple more significant points:

• There were significant differences in the mean number of platelet transfusions between the low vs. medium and low vs. high groups.
• While there were significant differences in the median post-transfusion platelet counts and median increase in platelet count after transfusion between the low vs. medium and low vs. high groups, there was no difference between groups in the median 4-hr corrected count increment.
• While the platelet dose had no significant effect on bleeding, the percentage of patients with bleeding of grade 2 or higher was significantly higher in autoHSCT (57%) vs. chemotherapy (73%) and alloHSCT (79%) patients.

This is a significant study that has the potential to change practice, especially because of the acute shortage of plateletpheresis products.  Unfortunately, this study does not address one of the most difficult problems in these patient groups--platelet refractoriness.  It would be valuable to have a study that showed that low dose platelets transfused to platelet refractory patients weren't any worse or associated with more adverse events than standard dose platelets.