Blood Bank Guy Blog

Plasma Transfusion Presentation

2012-02-22T11:46:00.001-07:00

I know that I owe everyone more than just a few posts. I'm working on some stuff, but in the meantime, I wanted to point you to an excellent online presentation from Dr. James Stubbs (Mayo Clinic) summarizing the poor effect of plasma transfusions on both laboratory correction of mild to moderate INR elevations and bleeding outcomes. You can view the presentation by clicking this text.

Keep watching this space for more posts to come.

Take Note!

2011-09-16T09:17:00.001-06:00

For the last 16 years, I have been privileged to be the primary transfusion medicine lecturer for the Osler Institute Pathology Review Course. I have interacted with thousands of pathology residents and practicing pathologists, and I'm convinced that I have taken more away from those interactions than I have given. One of the great things about doing the course is that it forces me to update my blood bank review notes on a regular basis. I'm happy to announce that the latest version is now available for download, at the bargain price of (wait for it....) FREE!

The notes are divided into five main sections, and include details about blood groups and immunohematology, blood donors and blood collection, component therapy, transfusion reactions, transfusion-transmitted diseases, and practical applications (yes, I know that is more than five, but some sections cover more than one thing!).

Every time I update the notes, I am amazed at how much I end up changing stuff. The world of transfusion medicine is fast-moving, and new information comes out all the time! This version includes more updates and changes than any version that I can remember in the last ten years, so I hope that you will check it out.

Finally, let me answer the question that I get quite often: No, I did not make these notes with the intention that they would be ALL you need to pass your board or other specialty exam. They are designed to be a supplement to any of the standard texts in blood banking, and to help you focus on what I have seen to be important in my many years of helping students prepare for exams. They are also designed to be a quick reference for practicing pathologists, nurses, blood bank technologists, and anyone else that needs quick access to the basics of transfusion medicine.

The full versions are completely and totally free, with no strings attached and no personal information required. I hope that they are useful to you! Please let me know if you find them helpful (or if you find errors or omissions).

You can download the notes at the Blood Bank Guy website today.

Don't Over-React!

2011-08-31T10:42:00.000-06:00

Some time ago, I published a chart on the Blood Bank Guy website that summarized the basic facts about the major transfusion reactions in a one-page, easy to carry, easy to memorize pdf file. I hadn't looked at it or really even thought about it for years, until someone recently e-mailed me and told me that it had been extremely helpful to him during his residency. I was horrified, to be honest, because I knew that it really was out-of-date! He assured me that he hadn't harmed anyone, and we parted as friends.

However, the e-mail conversation got me thinking about the chart, so I broke it out and looked at it again. I liked many things about it and was embarrassed about others, so I took the time to review each and every entry and update it with the most current information I have. Today, I am happy to announce that I am re-publishing a better, more clear, and up-to-date Blood Bank Guy transfusion reaction chart (you will have the best results by getting the chart on the BBGuy site, where it is in pdf format and you can print it yourself, or you can click the image below to see it now with lower resolution). As before, the chart is designed for quick reference, or for inclusion in your on-call notebook, or as a quick way to review stuff before an exam, or for whatever purpose you think fits best (paper airplanes, anyone?). I hope that it is helpful and useful to you!

G Whiz!

2011-08-11T11:08:00.001-06:00

As medical director of an AABB-accredited immunohematology reference laboratory, I and my colleagues get to see our fair share (or more) of complex red cell antibody problems. I am blessed to have a brilliant team of techs and leaders in the lab that handle most of these issues with ease, but I do get questions about red cell antibodies at work, on the Blood Bank Guy web site, and especially when I am giving blood banking review lectures. One of the most frequently asked goes something like this: "What the HECK (or words to that effect) is anti-G?!" If you have asked that question (even if it has been answered and you can't remember the answer!), this post is for you!

The Basics:
Any discussion of G has to begin with a basic understanding of Rh blood group system nomenclature and genetics. I have covered this on the Blood Bank Guy website, so if you aren't completely clear on Rh and how the terminology and genetics work, go now and check out the details (then come back, ok?).

The G Antigen:
The G antigen, unlike the main D/C/c/E/e group of Rh antigens, is present on any red cell that carries either the D or C antigen. This means that G is only absent when a person's red cells lack both D and C, as follows:

Phenotypes with G Present	Phenotypes with G Absent
D+C+ D–C+ D+C–	D–C–

According to the gene discussion on the BBGuy site, that means that a person will have G if they carry one of the following three alleles: RHD, RHCe, or RHCE. Referring back to the table of Dr. Wiener's terminology, I have placed all the haplotypes that would lead to G-positivity in red in the table below:

D Positive Haplotypes	D Negative Haplotypes
R₁: DCe	r': dCe
R₂: DcE	r": dcE
R₀: Dce	r: dce
R_z: DCE	r^y: dCE

It should be pretty obvious, then, that most people are G-positive, as the only genotypes that would result in someone being G-negative are rr, rr", and r"r" (rr is by far the most common combination of these three, and it occurs in around 15% of the US population; the other combinations are seen in less than 1% combined). Put another way, the vast majority of anti-G is seen in D-negative people who have the rr genotype.

NOTE: OK, to be fair, you should know that there are a very small number of D+C- people that lack G, as well as a very small number of D-C- people that have G.

Biochemically, expression of the G antigen depends on the presence of a common amino acid present on the surface of both D and C antigens. There is much more detail in that discovery, but I don't want to make your head explode, so let's move on to anti-G and its significance!

The G antibody (Anti-G):
Anti-G is an antibody formed in almost all cases by D-negative, G-negative patients with the genotype rr (dce), for reasons discussed above. The classic manner that anti-G is seen is in a D-negative patient who has never been knowingly exposed to Rh-positive blood, yet presents with an antibody that looks like a combination of both anti-D and anti-C (sometimes called "anti-CD"). This antibody can be induced either by pregnancy or transfusion, and most commonly results from exposure of an rr patient to blood from someone with either an r' or sometimes to an R₀ haplotype. Two examples of this are shown below:

In example 1 above, a D-negative patient is exposed to the G antigen through interaction with a D-negative-but-G-positive person who carries G as a result of the action of the RHCe allele (r' haplotype). This interaction could occur with pregnancy, and is also typical of a presentation seen after transfusion (such interaction, by the way, is completely unpreventable in transfusion, as the donor in this case would appear completely compatible with the recipient, and we don't routinely screen D-negative donors for the presence or absence of C antigen). Just glancing at the above example, you would not be surprised at the formation of anti-C, but the added anti-D specificity makes no sense unless you understand that G is present whenever either C or D is present.

In example 2 above, a D-negative patient is exposed to G through interaction with D-positive-C-negative-G-positive red cells, either deliberately during a transfusion (most commonly a massive transfusion), or as a result of pregnancy. Again, a cursory examination would not leave you surprised that the patient has an antibody with anti-D specificity, but the anti-C part of the specificity is only explained by the presence of anti-G. Please note that this is only one example, and any combination of D-positive red cell exposure (whether from donors with C as well, such as those with R₁ or R_z haplotypes or from those without, such as those with R₀ and R₂ haplotypes) could potentially lead to anti-G formation in this D-negative recipient. The difference is that you would not be surprised to find anti-C + anti-D in situations when a patient was exposed to both antigens.

Why do we care, anyway?
If you have made it this far, congratulations! You may be thinking, "Gee, Joe, the explanation makes a little bit of sense, but why do I care? What difference does it make if a patient has an anti-G or anti-D plus anti-C?" From the perspective of a patient who is about to be transfused, realistically, the distinction makes NO difference whatsoever. A patient with anti-G would be transfused in exactly the same way as a patient who has the combination of anti-D and anti-C: With D-negative blood. Remember, just about everyone who is D-negative has the genotype rr, meaning that they should be negative for D, C, and G (a transfusing laboratory would, of course, verify that the person was D- and C-negative before the transfusion).

The distinction is much more important, however, in prenatal workups. First, anti-G can be associated with hemolytic disease of the fetus/newborn (HDFN), though it tends to be milder than that caused by anti-D. Second, when a D-negative mother has antibodies that look like anti-D along with anti-C in the antibody screen that is a routine part of prenatal care, the laboratory must ask a very important question: Is this truly anti-D? The answer will determine the obstetrician's next step. If the antibody really is anti-D, the patient does not need to receive Rh Immune Globulin (RhIG) to prevent the formation of the antibody (provided the patient has not recently received RhIG). If the antibody is actually anti-G and NOT anti-D, however, RhIG is still indicated to prevent formation of anti-D. That important distinction brings us to the last portion of this discussion.

Separating anti-G from a combination of anti-C and anti-D:
If you really want to make your brain hurt, just ask an immunohematology reference laboratory technologist about how to separate anti-G from anti-C and -D; you will be running for the ibuprofen before you know it! You will hear about "double adsorptions" and "testing adsorbed eluates" and the like (my first mentor in immunohematology, the fabulous Connie Howard at the late great Walter Reed Army Medical Center, taught me long ago that I'm just too stupid to completely understand all of those details!). Let me try to make it easier for both you and I...with pictures!

Classically, immunohematologists would distinguish between anti-G and both anti-C and anti-D by the use of a procedure that pulled first one antibody out of the serum (adsorption), then isolated the anti-G by the use of a second adsorption procedure. That procedure is sometimes called "G-differentiation." Here's how it would look, using a patient that has all three antibodies (anti-D, anti-C, and anti-G):

Figure 3 represents part 1 of the identification. In this example, the test serum contains anti-C, anti-D, and anti-G. The adsorption is performed using D+G+C- RBCs (in an attempt to isolate the anti-D and anti-G and leave the anti-C behind in the adsorbed serum). In our example above, that attempt was successful, and an eluate of the red cells in this portion would contain anti-D and anti-G, but not anti-C. The next step is to elute (dissociate) the bound antibodies from the test cells and use the eluate (containing anti-D and anti-G) to perform a second adsorption (the "double adsorption" I mentioned above) with red cells of a different phenotype, as shown in figure 4 below:

Note that D-negative, G-positive RBCs are specifically chosen so that the only possible antibody that could adsorb to these cells (out of the original three that we were evaluating) is anti-G. The anti-G is then eluted from the cells and identified as anti-G by its activity vs. C and D positive RBCs. Here is the key to understanding the two figures above: If no anti-G is present, following the same steps with only anti-C and anti-D would leave you with a final eluate that was completely negative.

G-differentiation is, in all honesty, somewhat of a pain in the posterior to do! It is time-consuming and specialized, and as a result, some reference laboratories have modified their procedures to incorporate a bit of a shortcut. Think about it: The most important question for pregnant D-negative ladies in this situation is really: "Is anti-D present?" The presence of anti-G can be assumed if anti-D is not identified. This process is sometimes called "D-differentiation," and here's how it looks, with figures 5 and 6 showing adsorption testing of two different D-negative pregnant women:

D-differentiation appearance without anti-D

D-differentiation appearance with anti-D

Note that in figure 5, no anti-D is present. The technologist would test the adsorbed serum, note the lack of anti-D, and recommend the administration of RhIG (assuming that the pattern of anti-C plus anti-D was caused by anti-G). In the second example, in figure 6, anti-D is present in the adsorbed serum and would be identified on testing that serum, so the technologist would not recommend RhIG (though the presence of anti-D opens a whole new discussion about management of the pregnancy, etc).

Gasp! Wheeze! Choke! Sputter!

Seriously, you are still here? Wow, thanks! I apologize for the length of this post, but I felt it was important to be more thorough than most regular blood bank references, because so many people don't understand this topic. I hope that this was helpful. Feel free to comment below.

Thanks to Monica LaSarre and Cami Melland for helpful criticism and resource materials.

So Long, Walter Reed!

2011-07-22T12:13:00.000-06:00

I have been following the news of the impending closure of Walter Reed Army Medical Center in Washington, DC, from afar for several years. I have very mixed feelings right now about the whole thing.

I spent the majority of my time in the military, from 1991 to 1999, at Walter Reed, first as a pathology resident, and later as a staff pathologist and medical director of blood services. While I and everyone who has ever worked there would tell you that it was FAR from a perfect place, I can say with certainly that the medical and nursing staff that I dealt with were incredible! There was so much skill, so much caring, and so much passion for giving soldiers and dependents the best possible medical care that you couldn't help but go home every day full of pride. At the same time, the frustrations regarding cuts in support staff, facilities that were aging badly, and the results of seemingly millions of previous poor administrative decisions on everything from computers to lab equipment became exhausting.

Despite all of the frustrating parts of being at "Walter Wonderful," I can honestly say that my time there was among the most important and beneficial of my career. I was forced (sometimes against my will) to make leadership and medical decisions that I wasn't sure I was ready to make, and the resulting experiences have stayed with me and guide things that I do today. The Army was great to me, and my memories of Walter Reed are mostly very good.

If you read the article I linked above, you will see that the comment section contains thoughts about Walter Reed that are decidedly mixed. That is understandable. Anyone who spent any time there knows that the place had flaws, sometimes big glaring flaws. I would bet, however, that most of us would also say that we are better healthcare providers as a result of the experience we gained at Wally World. I will miss the place, and cherish the memories of the people that I knew there.

Total Eclipse of the...Virus

2011-03-31T15:11:00.008-06:00

Terminology can get a bit confusing when discussing different stages or "periods" of viral infections in relationship to transfusion-transmitted infections. I've tried to simplify some things in this post, to help you understand the differences between "windows" and "eclipses!

In October 2010, Morbidity and Mortality Weekly Report contained an alarming report of a case of transfusion-transmitted HIV. In reading this article (which was of very great interest to me because it involved a transfusion given in the state in which I live; though the blood product was not from the blood center where I work), I was struck by the author's use of the terms "eclipse phase" and "window period." These two terms are defined in the article, but they seemed really similar at first glance. (NOTE: I will use HIV as an example in the following discussion, but the terms apply generally)

According to the MMWR article, the eclipse phase of an HIV infection is defined as "the interval between infection and the development of detectable concentrations of HIV RNA in plasma," while the window period is defined as " the interval between infection and development of detectable HIV markers in blood." These definitions sound similar, but there is a very important distinction: A person may be infectious at points during the window period, but most people would say that person is not infectious, by definition, during the eclipse phase. In fact, it is probably easiest to think of the eclipse phase as being a part of the window period (some have even designated it as such, as in: "the eclipse phase of the window period") as shown in the figure below:

Example of the relationship between the window period and the eclipse phase

As you can see from the diagram, the part of the window period that we really worry most about is after the eclipse phase and before the end of the window period, since that is the only portion during which the donor is infectious for a particular organism.

I will admit, however, that you will find different definitions for these two time periods in published literature. Some of the definitions say that the eclipse phase is an infectious period, while others disagree. The MMWR report cited, in fact, seems to favor that definition. However, the majority of what I have been able to read cites the eclipse phase as noninfectious.

Into that mix we throw another term that can be confusing: Incubation period. The incubation period may or may not correlate with the window period. This time frame, unlike the window period, is not defined by positive laboratory tests. Rather, the incubation period is simply the time from exposure to an organism until the patient displays clinical symptoms. It can be shorter than the window period (good news for blood safety, as their symptoms manifest before they are infectious) or longer (which is typical for HIV).

Finally, the latent period/phase has been variably defined in the literature. It has been used to indicate the period after the eclipse phase and before the end of the window period (the time marked as "Infectious" on the chart above), but it is more commonly used in HIV infections as a term for an asymptomatic dormant period after infection, possibly after a mild manifestation of initial symptoms. The latent period may extend for years in some cases; that is certainly common in HIV.

I hope that helps a little bit. You can read more about each term by clicking the link, which will take you to the glossary section of the BBGuy web site. Here is a summary of the above:

Window Period: Period from infection until laboratory detection
Eclipse Phase: Period from infection cell until infectious virions assembled
Incubation Period: Period from infection until clinical symptoms
Latent Phase/Period:

After eclipse until infectious particles present outside of cell, or
Asymptomatic phase after infection when virus is still present and may be multiplying, or
Dormant period after initial infection when manifestations are not seen (HSV or VZV)

Perils of Poly(agglutination)

2011-03-14T17:04:00.004-06:00

OK, here's one for all you immunohematology geeks out there (I say that with all admiration and respect, by the way)!

Not long ago, the immunohematology reference lab at the blood center where I work received a sample for a lectin workup from a patient suspected to have polyagglutination. The patient was a child, and had recently been diagnosed with sepsis secondary to Streptococcus pneumoniae. This situation led me to think about polyagglutination and summarize it for you.

Polyagglutination is poorly understood by most students and even more poorly understood by most blood bank physicians. It is a situation in which red blood cells are agglutinated in the presence of virtually all human serum as a consequence of a change from normal that occurs on the surface of the red cell. This "change" is the exposure of antigens that normally remain hidden from view, either as a consequence of an infection or as an inherited disorder.

Multiple forms of polyagglutination (also called "activation") have been described, and they share one important feature: The not-normally-exposed exposed antigens (properly called "cryptantigens") are targeted by IgM antibodies present in the circulation of the vast majority of human sera. Those antibodies cause the diffuse agglutination of activated red cells, regardless of the ABO type of the red cells or ABO or other antibodies in the serum (thus, the designation "polyagglutination").

In general, polyagglutination is seen far less often in modern blood banks than in the past. This is largely due to the fact that the majority of cases of polyagglutination were suspected when a patient or donor had an ABO discrepancy on routine blood typing tests. Such findings were due to the reaction of the polyagglutinable RBCs against the antibodies (polyagglutinins) in most human serum (remember, pooled human serum was used in the past for ABO typing). Since monoclonal reagents are used for these tests today, cases of polyagglutination are not so obvious, and they usually are not noticed until human serum and red cells are mixed together in performance of an antibody screen, antibody panel, or crossmatch, or a suspicious clinician alerts the blood bank due to clinical symptoms.

It is easy to get overwhelmed in the sea of different types of polyagglutination, but I recommend that you just think of them in two categories: Acquired (which is most common) and Inherited.

Acquired Polyagglutination	Inherited Polyagglutination
T Activation Tk, Th, Tx Polyagglutination Acquired B	Tn Polyagglutination HEMPAS Sd(a++); Cad NOR

Acquired Polyagglutination
The most common and best example of this type of polyagglutination is known as "T activation." Also known as the "Hubener-Thomsen-Friedenreich phenomenon," this form of polyagglutination is seen most in children, primarily in those with bacterial infections. T activation occurs most often in association with infections with Streptococcus pneumoniae, Clostridium perfringens, or Vibrio cholerae, though the same findings can be present in influenza virus infections. Enzymes from the bacteria cleave sialic acid residues from glycophorins A and B, exposing the T antigen to full view (while also decreasing expression of MNS blood group antigens carried on the same glycophorin chains). Most of these patients have no symptoms, but occasionally, someone with T activation may present with hemolysis. More significantly, patients with T activation may suffer significant hemolysis when they are transfused with human plasma. Patients with T activation may require the use of washed cellular blood products to avoid hemolysis, but such use is transient, as this antigen change only lasts until the infection is cleared. T activation has a characteristic lectin reaction pattern (outlined below).

The other acquired polyagglutination entities outlined have unique features, but are all associated with characteristic infections and resultant cryptantigen exposure.

Inherited Polyagglutination
Tn polyagglutination is the classic inherited polyagglutination. It is caused by a mutation (likely on a gene on the X chromosome) that leads to poor synthesis of sialic acid residues on glycophorins A and B (with a corresponding MNS antigen decrease). As a result of the glycophorin A and B/MNS connection, it is easily confused with T activation. However, the two entities differ in several important ways. First, Tn polyagglutination is associated with much more serious clinical problems than T activation, including the common associated findings of hemolytic anemia, thrombocytopenia, and leukopenia. Second, in theory, Tn polyagglutination is lifelong (since it is inherited), as opposed to the transient nature of T activation. Third, the red cells in Tn polyagglutination are not uniformly agglutinated, leading to a characteristic "mixed field" agglutination pattern when mixed with human serum. Finally, both T and Tn cryptantigens may be over-expressed on malignant cells, but high Tn density on those cells has been associated with higher metastatic potential.

HEMPAS is an inherited hemolytic anemia in which the red cells undergo polyagglutination, associated with an antibody that can cause hemolysis of affected red cells at 37C. Sd(a++) cells (also fabulously named "super-Sid" or "Cad") are seen when individuals have an abnormally strong form of the Sd^a antigen, leading to polyagglutination. Individuals harboring these cells are not reported to show substantial resultant adverse effects.

Lectin Reactions
Lectins are at the core of how blood banks work up suspected cases of polyagglutination. It is important to note, however, that lectin reaction patterns are not to be used as the only arbiter of a specific type of polyagglutination. Clinical and laboratory data are also a large part of the workup. With that being said, here are some classic reactions with various lectins, patterned after Daniels, Human Blood Groups, 2nd ed., page 525, and Reid, The Blood Group Antigen Facts Book, 2nd ed., page 545.

Lectins	T	Th	Tn	Cad
Arachis hypogea	+	+	0	0
Glycine max (soja)	+	0	+	0
Salvia sclarea	0	0	+	0
Salvia horminum	0	0	+	+
Dolichos biflorus	0	0	+	+

Many thanks to Monica LaSarre and Colleen Chiappa, two of the geniuses at the Bonfils Blood Center Immunohematology Reference Laboratory, who helped fact check this post. Anything smart written here should reflect their brilliance, while any errors are surely mine.

Feeling Positive?

2011-02-21T13:46:00.006-07:00

Is a donor "reactive" for a particular infectious disease marker or is he "positive"? What does "repeat reactive" mean? Can you have a reactive test on a particular sample and still be categorized as "non-reactive"? When studying transfusion-transmitted diseases (podcast on this topic coming soon), you will read terminology that can sometimes be confusing to non-virologists of the world (I proudly include myself in that category!). This blog entry will discuss several confusing terms related to viral marker testing results.

I think the first "rule" that you should understand for discussing terminology is the following: There really aren't any rules! While what I am about to outline below is fairly standard, reading through the package inserts of the FDA-approved infectious disease screening tests shows some definite variation. However, I think what follows will serve you well in most situations.

As you are probably aware, for most blood donor testing, a screening test is used first, followed by a confirmatory test if the screening sample shows evidence of a potential transfusion-transmitted disease. For screening tests (most of which are either EIA or ChLIA), testing labs follow a fairly well-defined routine.

If a donor's test results fall below the threshold defined by the manufacturer, the donor is by definition "non-reactive" (NR) for the marker in question, and no further testing is done. The donated unit is released for transfusion (provided all the other disease marker tests are negative, of course!).
If a donor's test results fall above the manufacturer-defined threshold, the donor is by definition "initially reactive" (IR) for the marker in question. The sample will be re-tested in duplicate to further characterize the donor's results. The donated unit will not be released until the issue is resolved.
If either or both of the donor's duplicate repeat results fall above the manufacturer-defined threshold, the donor is by definition "repeat reactive" (RR) for the marker in question (this generally leads to deferral of the donor for a variable period of time or forever and destruction of his donated unit).
If, however, both of the donor's duplicate results fall below the manufacturer-defined threshold, the donor is by definition "non-reactive" for the marker in question (yes, exactly as if his result in the first bullet above was below the threshold). Just as in the first bullet above, the donated unit would be released for transfusion if there is no other disqualifying issue.

So, for screening tests, in general, the terminology used is "reactive" or "non-reactive" rather than "negative" or "positive." The opposite is generally true of confirmatory testing. So if, for example, a donor tested repeat reactive on the anti-Hepatitis C Virus (anti-HCV) test, his sample would usually be processed for the confirmatory test for anti-HCV, known as RIBA (recombinant immunoblot assay). If the RIBA results fall into a specific pattern, the results are "positive" and the donor is considered "positive" for anti-HCV.

NOTE: A strange little exception to this is with Nucleic Acid Testing (NAT), which is used for HIV-1 and HCV (and in some cases, though not yet required, for Hepatitis B Virus). NAT seems to fall into an intermediate category with terminology, and when you read the package inserts from the manufacturers, you will see that the result syntax is not consistent. Some use positive/negative, some use reactive/nonreactive.

General Summary: Donor screening tests are reactive/nonreactive. Donor confirmatory tests are positive/negative. Donors themselves, after testing, are positive/negative for disease.

XMRV-An Emerging Infection Case Study

2011-02-09T17:37:00.010-07:00

In the early 1980’s, physicians in San Francisco and New York were puzzled by a growing number of aggressive cases of a rare malignancy known as Kaposi’s sarcoma, as well as a rare lung infection, Pneumocystis carinii (now "jirovecii") pneumonia. These illnesses were discovered initially in homosexual men, but were later seen in a growing number of patients suffering from hemophilia.

We know now, of course, that the illness in question was Acquired Immune Deficiency Syndrome (AIDS), and that the causative agent, Human Immunodeficiency Virus (HIV), had been unknowingly transmitted to a number of hemophilia patients through blood products from infected donors. In the decades that have passed since that disastrous time, numerous blood donor policies have been established and decisions made (both appropriate and inappropriate) based largely on the blood banking industry’s desperate fear of repeating the HIV experience. The Xenotropic Murine Leukemia virus-related Virus (XMRV) crashed headlong into that backdrop recently, and the full effect of its appearance is still unclear.

XMRV is not, by strict definition, a “new” virus. It was actually discovered in 2006, in association with a rare, hereditary form of prostate cancer. In what will become a recurring theme in this discussion, however, many subsequent studies showed a much less definitive link between the virus and prostate cancer. Despite this, the virus’ characteristics were well studied soon after its identification. XMRV is related to a group of similar-appearing viruses that cause leukemia in mice and also infect other species (Murine Leukemia Viruses, or MLV; thus the last part of the name “Murine Leukemia Virus-RELATED virus”). The fact that XMRV infects humans makes it “xenotropic” (definition: originating in one species and causing disease in another). Like HIV, XMRV is a retrovirus, but it is a different type of human retrovirus than HIV (so-called “gamma retroviruses”). Like all retroviruses, XMRV infects cells by translating its RNA into DNA, which then integrates into the host cell genetic material and causes manufacture of new virus particles. It should be noted that XMRV, despite its name and status as a retrovirus, has no association with either leukemia or AIDS-like immune defects in humans.

XMRV became much more widely known because of a 2009 report of a potential association with Chronic Fatigue Syndrome (also known as “myalgic encephalomyelitis” and abbreviated as “CFS-ME” or just “CFS”). CFS is an illness that is more severe than its rather benign-sounding name. CFS patients are not just “tired”; they are nearly debilitated by extreme fatigue, in association with sleep disturbances, cognitive impairment, flu-like symptoms, and muscle pain (“myalgia”), all lasting at least six months. Millions of people (mostly women) around the world are believed to suffer its effects. Some researchers and clinicians have suggested over the years that CFS may be caused by an infectious agent, but until 2009, concrete evidence of such an association was lacking. Dr. Judy Mikovits and her colleagues at the Whittemore Peterson Institute (Reno, NV), National Cancer Institute, and Cleveland Clinic published a paper in Science in October 2009, noting that 67% of the 101 patients with CFS they tested had detectable XMRV genetic material (vs. 3.7% in controls). This finding led the group to suggest that “XMRV may be a contributing factor in the pathogenesis of CFS.”

Throughout the early portion of 2010, several international research groups unsuccessfully attempted to confirm the results reported by Dr. Mikovits and colleagues. However, in August 2010, a study ~~sponsored by the U.S. Centers for Disease Control (CDC)~~ led by Drs. Lo and Alter, performed in labs at the FDA and the U.S. National Institutes of Health (NIH), showed similar but even more impressive XMRV-CFS associations than the previous paper. The CDC study reported XMRV sequences in almost 90% of CFS patients, seemingly confirming the earlier study’s result. More recently, however, to complicate matters, four separate studies published in Retrovirology in December 2010 cast doubt on the whole XMRV-CFS association by reporting data suggesting that XMRV sequences could be simply contaminants rather than true pathogens (this claim was strongly denied by Dr. Mikovits, among others). Working groups from the U.S. Department of Health and Human Services and AABB are actively trying to sort through all the conflicting data and test methods at this writing.

Those of us in the worldwide blood industry responded to these revelations with varying speed. Most had immediate concern that XMRV could be transmitted through transfusion (a fear that is currently unproven). As a result, throughout 2010, many countries (including the United Kingdom, Australia, Canada, and New Zealand) moved to prevent donors who volunteered that they have or had CFS from donating blood. In the U.S., AABB likewise recommended a voluntary self-deferral of donors diagnosed with CFS (so-called “active discouragement”) in June 2010 (click for more details on AABB's position); that policy is still the most active form of CFS screening in the U.S. at this writing. Donors are not asked a specific question about having CFS on the standard donor questionnaire at this time. Many in the lay press and several patient advocate and blood safety groups have sharply criticized the U.S. Food and Drug Administration (FDA) and the blood industry for not acting specifically and definitively to permanently defer all donors with CFS from blood donation.

So where do we stand with XMRV? The answer is really quite simple, but unsatisfying: We just don’t know for sure yet! The data, as outlined above, is conflicting, but the pressure on the blood industry to “do something” (partially external and partially self-imposed) seems to be mounting. In December 2010, the Blood Products Advisory Committee (BPAC) of the U.S. FDA heard presentations from the AABB task force mentioned above, as well as from representatives of the infectious disease testing industry and an advocate for patients with CFS. BPAC rejected the task force recommendations that voluntary self-deferral was adequate, and voted to recommend that FDA require a specific question about a history of CFS on the donor questionnaire by a vote of 9 to 4. FDA has not formally mandated such a question at this time, however. The reality is that we don’t even have a good way to test for the virus at this point, nor is there conclusive evidence that we need to do anything beyond what is already being done to discourage individuals with CFS from donating blood.

The XMRV-CFS association and its subsequent effect on the blood banking industry is a great example of how difficult decisions can be in the HIV-influenced world we now inhabit. The “what do we do and when do we do it?” questions are challenging both ethically and scientifically, especially when the evidence is developing and sometimes conflicting and the answers are unclear. It seems that many in the public arena and in the blood industry, following the HIV calamity of the early 1980’s, have embraced the so-called “precautionary principle” when considering the possible effect of a new infectious agent. This principle, as stated in 1998, is: “When an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically”. However, in the current environment of limited resources and a seemingly endless flood of emerging and novel infectious agents, those of us in this industry are put in the difficult position of trying to make wise choices based on limited information and evidence, making our best efforts to balance incomplete information and unease about the unknown with the desire to protect our recipients and donors as best we can.

Updated on 2/10/11 to correct laboratories for Lo and Alter study.
Updated on 2/21/11 to correct Pneumocystis name.

Hepatitis C Testing

2011-01-29T15:33:00.009-07:00

I recently received a question from a friend at a hospital-based donor center regarding re-entry testing for a donor that had a previous reactive test for Hepatitis C virus (HCV). The rules have recently changed regarding how to re-enter people in this situation, so it seemed like a good opportunity to write about the overall HCV testing strategy in U.S. donors, with an emphasis on those recent changes.

Post-transfusion hepatitis has been known to the medical community for well over half a century. Hepatitis B (HBV) was discovered in plasma and transfusion recipients during and after World War II, and the discovery of Hepatitis B Surface Antigen (HBsAg) in the 1960's quickly led to blood donor testing for HBV. To the disappointment of blood bankers of that era, however, implementation of HBV testing only prevented a minority of post-transfusion hepatitis cases. Everyone knew that there was another agent at work, and that agent (which we now know to be HCV) caused what was called "non-A, non-B hepatitis." After years of investigation, the Hepatitis C Virus (HCV) was finally identified in 1989.

HCV causes problems in recipients for several reasons. First, it is fairly efficiently transmitted through infection, meaning that there is a very good chance that a recipient of HCV-infected blood will in turn be infected. Second, most HCV infections are asymptomatic for a period of years, so someone who is infected via transfusion may not know that they are infected until very late in the disease. Finally, HCV is notorious for chronic, long-standing infections that lead to serious complications twenty or more years after infection (including cirrhosis and in some cases hepatocellular carcinoma).

Testing strategies for most potentially transfusion-transmitted infections tend to fall into one of two categories:

Testing for the body's response to the agent
Testing for the presence of the agent itself

HCV testing, like most blood donor testing, began with the indirect testing method of finding antibodies against HCV. These tests are either enzyme immunoassays (EIA) or related chemiluminescence assays (ChLIA); when I refer to "anti-HCV EIA" below, I am including both methodologies. They were developed fairly rapidly after the identification of HCV in 1989, and were mandated by the FDA in 1990. The tests have improved from the original "1.0" version to the current "3.0" versions (which simply utilize more and more pure HCV antigens in the test to better detect HCV antibodies against different parts of the virus). The confirmatory test used whenever a reactive EIA/ChLIA is seen is known as RIBA ("recombinant immunoblot assay"). In 1999, blood centers began performing direct testing for HCV utilizing various forms of PCR, collectively referred to as "nucleic acid testing" (commonly called NAT; not "NAT testing" because you'd be saying "nucleic acid testing testing" and that's redundant and stupid-sounding, ok?). NAT is very sensitive and specific, but it isn't completely perfect. Testing each and every donor individually (individual donor NAT or ID-NAT) would be exceptionally expensive, so virtually all U.S. blood centers pool samples from 16 to 24 donors and test them all together (this methodology is approved by the FDA, by the way). Doing this is known as "mini-pool" NAT (MP-NAT), and it is slightly less sensitive than ID-NAT, but not markedly so. Positive MP-NAT leads to testing of all donors in the mini-pool with ID-NAT to determine which donor is positive.

A donor that is truly infected with HCV is usually reactive for both the EIA (with positive RIBA) and HCV NAT. Fortunately, in most populations, that doesn't happen very often anymore. The problem comes when a donor is positive for some, but not all of the tests mentioned above. How are those donors managed, and can they ever donate again? Fortunately, the U.S. FDA came out with a guidance document covering these issues in May 2010. Unfortunately, the guidance is really hard to read and is confusing in some places. Let's walk through some testing result possibilities and their consequences:

Anti-HCV EIA repeat reactive, RIBA any result, HCV NAT reactive

FDA does NOT allow these donors to ever donate again. They are "permanently deferred."

Anti-HCV EIA repeat reactive, RIBA positive, HCV NAT reactive OR nonreactive

FDA does NOT allow these donors to ever donate again. They are "permanently deferred." Note that most donors in this situation will be NAT-reactive, but as many as 10-30% will NOT have a reactive HCV NAT.

Anti-HCV EIA repeat reactive, RIBA negative or indeterminate, HCV NAT nonreactive

These donors are "indefinitely deferred", but are eligible for re-entry consideration after SIX MONTHS from the donation date

Anti-HCV EIA nonreactive, HCV NAT reactive

These donors are "indefinitely deferred", but are eligible for re-entry consideration after SIX MONTHS from the donation date

The first two categories are pretty easy to understand. In short, a confirmed anti-HCV EIA results in permanent deferral, as does a repeat reactive anti-HCV EIA in combination with a non-reactive NAT. In either case, recipients of previously donated blood products from these individuals must be notified (a process called "lookback" that I will leave for another discussion). I think that those make sense. The last two categories are a little more difficult, though.

The donor who tests repeat reactive for anti-HCV but does NOT confirm that result with a positive RIBA AND has a non-reactive HCV NAT probably is not infected with HCV. FDA recognizes that fact, but requires a waiting period before such a donor can even be considered for testing to regain his eligibility. This is because donors in this category most likely do not have HCV, but a small minority may be infected. The same general principle applies to those in the last category, with ONLY a reactive HCV NAT.

Please note that there is no requirement that these donors MUST be re-tested; centers are free to say "the heck with it, this is just too complicated" and permanently defer the donor without hope for regaining their eligibility.

If a center decides to embark on HCV re-entry testing, the donor is tested after six months using both a licensed anti-HCV EIA/ChLIA and an individual donor HCV NAT (ID-NAT). The donor is NOT allowed to donate a unit of blood in conjunction with this testing. If the testing is completely negative, then the donor may be re-entered into that center's system as an eligible donor. Obviously, the donor will be tested again with his first post-re-entry donation, so a total of two HCV NAT (at least one of which is ID-NAT) and two anti-HCV EIA/ChLIA tests will have to be negative before that donor's blood is transfused to anyone. Of course, the question that always comes up is this: What if the donor is NOT negative on the re-entry testing? Well, if the testing pattern is that of categories 1, 2, or 4 outlined above, the donor is permanently deferred (note that this is different for category 4 than the way we originally handled those donors). If the results fall into category 3 (if the RIBA, which is not required on re-entry testing, is performed), then the donor MAY continue down the re-entry pathway, with further testing after another six months. I can tell you that I personally do not offer an endless cycle of re-entry testing. For me, if a donor has anything reactive on the re-entry testing, I consider them permanently deferred.

One other potential complication: Sometimes, donors do not want to wait for six months to get tested, and sometimes pressure centers into getting a re-test sooner. There is nothing wrong with doing so, but those results, if negative, cannot be used to re-enter the donor. Even if the testing is done at 5 months and 25 days after the original positive donation, the donor will have to tested again and found negative after six months. On the other hand, if the donor tests POSITIVELY for ID-NAT during that six month waiting period, FDA recommends permanent deferral of that donor.

HCV testing has greatly advanced in the 21 years since the first anti-HCV test was implemented. Those advancements have led to great improvements in blood safety. At the same time, they have complicated donor management significantly, as outlined above. Hopefully, this very long blog entry will help you get a better grasp on HCV testing in its current state.

As always, comments are welcome below.

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CMV, Serologic Testing, and Leukoreduction

2011-01-19T12:42:00.003-07:00

For years, blood bankers and physicians have debated the relative merits of preventing CMV infection through the exclusive use of blood from donors who do not have demonstrable anti-CMV antibodies vs. blood that is leukocyte reduced. The data is mixed, and the two methods seem to be nearly equivalent (and imperfect). Why both fail at roughly the same low rate (about 1-4%) has never been particularly clear to me, until recently.

Background: Cytomegalovirus (CMV) is a human herpes virus that is extremely common in the United States (and elsewhere). At least 50% of blood donors have been infected at one point or another, but in healthy people, that is no big deal. In people that have compromised immune systems, however, such as CMV-negative solid-organ and progenitor cell transplant recipients and premature neonates, CMV can be absolutely devastating. Potential consequences include overwhelming hepatitis, retinitis, and pneumonitis, and if transmitted to a fetus by an infected mother, can result in mental retardation, blindness, deafness, and death.

Given the above, it is clearly incumbent on blood banks to provide blood that has as little risk as possible to those most susceptible to CMV's effects. As above, this includes those with substantially compromised immune systems, as well as those expected to have significant compromise soon (chemotherapy patients and those about to start preparation for a progenitor cell transplant, to name a couple).

Traditionally, in these settings, clinicians would simply order "CMV-negative" blood, and that is what blood banks would try to provide. "CMV-negative" (or "CMV-seronegative") simply means that the donor has been tested and is negative for the presence of anti-CMV antibodies. This process is not enormously difficult, but it can be difficult to find blood for a particular patient that has the appropriate testing sometimes. As a result, the blood bank industry looked for an option, and when a major study was published in 1995 in Blood (Bowden, et al), we thought we had nailed it! That study compared the use of CMV-negative blood products with blood that was leukocyte-reduced, with near equivalent results (the logic behind this is explained in an FAQ on the bbguy site).

Since the Bowden study came out, there has been much debate and much back and forth on this issue, with the discussion between the blood bank and clinicians usually going something like this:

Clinician: "I'd like CMV-negative blood for my patient, please"
Blood Banker: "You know, leukoreduced blood has the same risk as CMV-negative blood"
Clinician: "I'd like CMV-negative blood for my patient, please"
Blood Banker: "The AABB considers them equivalent"
Clinician: "I'd like CMV-negative blood for my patient, please"
Blood Banker: "I'll have to try and find some; I stopped testing last year"
Clinician: "I'd REALLY like CMV-negative blood for my patient, please"

You get the idea. Blood bankers like the leukocyte reduced idea, while clinicians tend to favor the seronegative option. As I mentioned above, however, it is important to recognize that both methods fail, and at about the same rate (1-4% or so). I recently read a discussion of this issue in a new edition of a book from AABB Press called Transfusion Therapy: Clinical Principles and Practices (3rd ed) that shed new light on this issue for me. I am indebted to that book for the rest of this discussion.

Let's take a second to understand how each method works, and describe the weakness of each test.

CMV serology testing: A fairly sensitive and specific enzyme immunoassay or hemagglutination assay is used to detect antibodies against CMV. Either test is good and reliable, but our main problem is with acutely infected donors that have not seroconverted yet ("window period" donors). Main method vulnerability: Window period infections.
Leukocyte reduction (LR): LR is thought to work for CMV prevention because in established CMV infections, the virus is limited to a small number of monocytes (1 to 25 CMV-infected cells per million white cells) and isn't floating around free in plasma. LR is so efficient at removing all WBCs (99.99% or more using currently available technology) including monocytes means that the load is reduced below infectious levels. If, however, CMV was free in plasma, LR would have essentially NO preventive effect. Main method vulnerability: CMV in plasma.

As it turns out, there is significant overlap between these two vulnerabilities, and that overlap is obvious when we analyze the acute stage of CMV infection. During the first 6-8 weeks after infection, no antibody is detectable because the body has not yet responded (the window period). In addition, during those 6-8 weeks, CMV actually does circulate in plasma ("viremic stage") in substantial numbers. As a result, it seems clear that the acutely infected, window period, viremic donor has an infection that could elude either method, potentially leading to CMV disease in a susceptible recipient. In other words, the most likely donors to give failures of either method are from exactly the same group! As a result, several authors have suggested that the "safest" blood may actually be from those donors that are CMV-positive (indicating an established infection and avoiding the window period) AND leukocyte reduced (removing the small numbers of infected cells). I don't think that strategy is popular at this point, however!

Bottom line: Both methods are good for CMV transmission prevention, and the methods are probably equivalent in non-acutely infected donors. Chances are good that the failures would be failures no matter the method used, according to the discussion above. I believe that individual facilities must have the discussion about how they will handle this, however, and stick to that policy (whichever method is favored). My personal belief is that the two methods are interchangeable, and that is usually my advice to inquiring blood bankers and clinicians.

Cellular Therapy Introduction

2011-01-11T16:41:00.010-07:00

If you ask anyone working in blood centers around the world about the "next wave" of new technology in the blood industry, chances are very high that you will hear the words "cellular therapy" somewhere in the conversation. Unfortunately, many people who talk about cellular therapy have only a vague understanding of what it encompasses, and many novices or trainees in the field don't have the foggiest idea what it means! This entry will take a quick look at cellular therapy and how it impacts transfusion medicine.

According to a recent article in Transfusion, cellular therapy (CT) is defined as "the varied use of mononuclear cells (MNCs), CD34+ stem cells, or lymphocytes to treat or prevent various types of diseases." (Snyder E and Choate J "The emergence of cellular therapy: impact on transfusion medicine" TRANSFUSION 2010;50:2301-2309). Cellular therapy is, in many ways, a logical extension of traditional blood banking, in which we simply remove blood from a donor and infuse it into a recipient with only a minimum of modification. Emerging forms of CT instead rely on the ability to manipulate and select certain specific cell types and sometimes treat them in very specific ways before infusing them into a recipient. Another difference between CT and basic transfusion therapy is that CT involves the infusion of a product that is designed to do something substantial and potentially radical once it is infused (such as repopulate a bone marrow, destroy a malignancy, regrow an organ, repair a tissue, etc.), while transfusion therapy is more focused on supplying components that function in supporting processes already going on in the body (carrying oxygen, facilitating coagulation, platelet clot formation).

The earliest examples of cellular therapy were seen in the transplantation of bone marrow to patients with hematologic malignancies, beginning around the 1940's or 1950's (with variable levels of success). These methods were rather crude, and simply used whatever cells could be harvested directly from a donor's bone marrow.

Many modern forms of CT, on the other hand, rely on apheresis technology to separate and harvest a specific group of cells. In addition, researchers have now developed methods to specifically stimulate the production of bone marrow stem cells (specific cytokines such as granulocyte colony-stimulating factor or "G-CSF"), as well as the ability to detect them in the harvested product (through detection of CD34on the surface of the cells).

The above developments made possible the widespread use of the most basic form of cellular therapy: Stem cell transplantation (sometimes known as "progenitor cell" transplantation). A multitude of disorders can be treated by stem cell transplant, including many hematologic malignancies and pre-malignancies as well as numerous genetic metabolic, hemoglobin, and immunodeficiency diseases. The basic principle involves the destruction of the patient's own marrow elements (often in concert with destruction of malignant cells) followed by the infusion of the stem cell transplant material designed to re-populate the marrow. The stem cells can be harvested from the peripheral blood using apheresis technology (most common), from a donor's bone marrow, or, in growing frequency, from umbilical cord blood. An in-depth discussion of these different methods is beyond the scope of this blog, but if you are interested, check out the discussion here.

The emerging and future directions of CT are far more broad than just transplantation, however, including opportunities to collect cells that will be used to design and manufacture patient-specific "vaccines" for different types of tumors as well as cells that may be used to generate or regenerate missing or damaged organs or blood vessels. One such treatment, for advanced prostate cancer, was approved recently. For that therapy, the patient undergoes leukapheresis according to exacting criteria, and the harvested antigen-presenting cells are stimulated in vitro by exposure to prostatic acid phosphatase (PAP). The cells are then reinfused, presumably primed to attack malignant cells expressing PAP. While this is the first example of an FDA-approved autologous cellular immunotherapy, numerous clinical trials are in process for other vaccines for other malignancies such as ovarian, cervical, and breast cancers (just for fun, go to the NIH's clinicaltrials.gov website and search for "immunotherapy"; you will be surprised how many active trials you find!).

Some other exciting uses of cellular therapy under study and development include methods to repair damage to organs and tissue. This type of CT is generally known as regenerative medicine, or tissue engineering. These methods may eventually prove useful in treatment of stroke victims, heart attack victims, babies with congenital heart abnormalities, and diabetes, to name just a few. Again, there's a lot more detail to this than I can cover here! For more information, you can take a look around at RegenerativeMedicine.net.

Future advances in cellular manipulation technology could conceivably result in the ability to manufacture patient-specific red blood cells or other blood components. Such changes are seen by some blood bankers as potentially devastating to our industry, but this is better looked at as a way for us to re-align and change what we do in such a way as to be ready for and embrace such new technology. Of course, the field of cellular therapy is growing and changing so rapidly that we will have to be very light on our feet and adapt quickly, but that's what makes it fun!

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Volunteer?

2011-01-07T01:02:00.012-07:00

When is a "volunteer" really a volunteer? For blood donor centers, this is a hugely important question to ask, since keeping an all-volunteer blood supply has been considered a mainstay of transfusion medicine for at least the last 25 years. I attended an interesting lecture today given by an incredibly knowledgable person (Gina Ramirez, manager of regulatory affairs) at the blood center where I work, and thought I would share some information from her lecture and my thoughts with you here.

The first thing that you have to understand is that, contrary to what you might think, the FDA actually does NOT prohibit the use of blood from paid donors! Since 1978, however, FDA has required the labels on blood products to specifically state whether the blood came from a paid or volunteer donor (see image below for an example).

Standard ISBT blood label; note "volunteer" designation

So, while it is not mandatory for blood to come from a volunteer donor, the reality is that there is really no market for blood centers to sell blood products from paid donors. No hospital that I know of would be happy to give blood labeled as from a paid donor, so for all intents and purposes, blood centers must keep our volunteer donors clearly in the category of "volunteers"! I think that this is the right idea, by the way, as it is just logical that someone who is paid to donate has an obvious incentive to make sure that he says whatever he needs to say to be allowed to donate.

SIDE NOTE: Please understand that this discussion is limited to blood products that are those to be transfused. Plasma donations that are to be made into source plasma for further manufacturing are not included in this rule, and these donors are paid regularly. I experienced this first-hand, as I was able to eat huge amounts of Taco Bell food in college as a result of selling my plasma!

The US FDA has actually looked at this pretty seriously, and they have published a summary of their general guidelines on their website (click to check it out). The rules of "paid" vs. "volunteer" labeling are also covered in the Code of Federal Regulations, 21 CFR 606.121 (c)(5). According to the FDA, a "paid donor" is one who has "received a monetary payment for a blood donation," and a volunteer donor as one who has not received such a payment. While that sounds simple, it isn't always easy. For example, most blood centers offer "donor incentives" like free t-shirts. Is a t-shirt a payment? What if the dude turns around and sells the shirt on eBay? What about a center that is giving away free baseball or football game tickets? How do you decide?

To the FDA, the main factor in this decision is the answer to the following question: Can the incentive easily be converted into cash? To answer that question, they recommend three additional questions:

Is the incentive transferable? The assumption here is that if an item cannot be used by another person, it can't be readily sold and converted to cash.
Is the incentive refundable or redeemable for cash? Same logic here, basically. FDA does not want a situation where a donor gets a gift certificate, for example, then converts that gift certificate to cash.
Does a market exist for the incentive? In other words, can the donor reasonable expect to sell the incentive? Chances are, the t-shirt I mentioned above would NOT elicit any bids on eBay, but the football tickets, on the other hand, might fetch a pretty penny!

FDA has actually ruled on several incentives that they deem clearly acceptable for volunteer donors across the board, as follows:

Time off from work
Membership in blood assurance programs (less of an issue in today's environment)
Cancellation of non-replacement fees (rarely an issue in today's environment)
Lotteries or raffles, regardless of value!
Non-monetary awards associated with product promotion

They also, in the linked article above (which is actually part of the "Compliance Policy Guide" used by FDA investigators in facility assessments), give some examples of commonly seen situations, and their thoughts on the volunteer vs. paid question. Here are a few of them:

Medical tests at the time of donation. It's really common for centers to offer free cholesterol testing or free PSA testing for male donors at the time of donation. In general, this is ok when the blood is drawn from that donor right at the time of donation. Vouchers that could be transferred to someone else; not so good!
Gift cards/gift certificates. This one is tougher, as the use of gift cards by blood donor centers has become much more common in recent years. FDA believes that gift cards are ok as long as they can't be converted into cash and can't be transferred (as my friend Gina said, it's not ok if a donor can take a $20 gift card, buy a pack of gum, and get $19 change in cash!). FDA does not specify a maximum dollar value at which "ok" becomes "not ok."
Tickets. This one has lots of gray area. As mentioned above, free tickets to sporting events are usually frowned upon by the FDA as incentives for volunteer donors. The secondary market for selling sports tickets is robust, easily accessed, and often has high demand; this combination makes it awfully easy to sell such tickets and convert them to cash (one option my center has used is to work with the team to print "zero dollar value" on such tickets, which makes it harder to sell the ticket to anyone with a brain!). Movie tickets, in the FDA's eyes, however, are much less of an issue, since scalping movie tickets is not usually successful!
Escalating incentives. This describes a scenario where the incentives get more valuable the more the donor donates. First donation, t-shirt; second donation, ice cream pint; third donation, A NEW CAR!! Technically, FDA says that the donations up to the one where the incentive failed the test for volunteer donors (that would be the third donation, in case you didn't notice!) could be labeled as from a volunteer donor, but the shady donation gets a "paid donor" label (I think that accepting the first two as volunteer is ludicrous, by the way! If a donor knows that her third donation will get her a new car, she clearly has incentive to be untruthful in the first two).
Scholarships. I think that I went to the wrong school, because I never heard anything like this, but apparently, certain centers offer scholarship programs to young blood donors. This one seems weird to me, but FDA says that such a program is OK as long as the student never puts his hands on the money. In other words, if the scholarship goes directly to the school, and the student has no access to it, FDA is ok with the donor being called "volunteer."

Anyway, these are just a few examples. My personal philosophy is that I like to keep things simple; I really try to stay far away from the edges of this issue. I'm totally good with t-shirts, coffee mugs, cookies, juice, Cheetos, Doritos, Cheez-its, and maybe the occasional ice cream sandwich (I'm hungry, how about you?), but I don't really like the idea of gift cards, NFL tickets, or NEW CARS!!! I also prefer to offer incentives (even the small ones) to everyone that presents to a blood drive or collection facility, even if they don't qualify to donate (that helps to eliminate some incentive to be untruthful, I think).

Feel free to comment below if any of you feel differently.

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Fluid Choice for Plasma Exchange

2011-01-03T16:59:00.006-07:00

Situation: A blood center receives requests for large volumes of group B plasma from two separate hospitals for plasma exchange. The center supplies plasma in three main forms: 1) Plasma frozen within 24 hours (FP24) from male donors and never-pregnant female donors, 2) FP24 from female previously pregnant donors, and 3) As cryo-reduced plasma, made exclusively from male and never-pregnant female donors.

This is based on an actual event that occurred during a period of critical shortage of group B plasma, especially from category 1 above. Further investigation revealed that one of the patients (patient A) had a diagnosis of thrombotic thrombocytopenic purpura (TTP), while the other (patient B) was recently diagnosed with multiple myeloma with hyperviscosity. In both cases, the clinicians involved were asking for plasma from category 1 above (with a presumably reduced risk of transfusion-related acute lung injury or "TRALI").

The blood center discussed the issue with the clinicians involved in both cases. We partially supported the request for FP24 from males/nulliparous females for patient A, but did not support it for patient B. Details follow...

TTP is a well-established indication for the use of frozen plasma (either FP24 or FFP) as an exchange fluid. TTP is caused by a usually acquired deficiency of ADAMTS13, an enzyme that metabolizes von Willebrand factor (vWF) from "ultralarge" to smaller fragments. The lack of this enzyme leaves vWF in the ultralarge form; this form of the protein stimulates platelet thrombus formation and damage to the red blood cells, brain, and kidneys. The standard treatment is replacement of the "bad plasma" with plasma containing normal levels of ADAMTS13. The best source is FP24/FFP. In my opinion, plasma from any of the three categories above is acceptable for this patient. That from category 2 (from previously pregnant females) does carry a slightly increased risk of causing TRALI, but the mechanics of plasma exchange, where plasma is given and removed on a rapid basis during the exchange, decreases the likelihood of TRALI substantially. In this setting, a mixture of plasma from category 1 and 2 works just great. Cryo-reduced plasma is acceptable, as well, as this product may help with patients with TTP due to the decreased level of all forms of vWF present.

Most non-TTP indications for plasma exchange (including myeloma), do not require FP24/FFP replacement fluid unless the patient has an underlying coagulopathy. The vast majority of these exchanges utilize albumin as replacement fluid rather than frozen human plasma. The majority of the exchanges in these situations are not done repeatedly over multiple days, and most patients tolerate the lack of coagulation factor replacement without a problem. If necessary, for repeated exchanges, a mixture of FP24/FFP and albumin can be used.

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Welcome to My Blog!

2011-01-03T00:50:00.008-07:00

Hi, and welcome to the Blood Bank Guy blog! It is now 2011, and following the lead of my friend Keith Kaplan, MD (www.tissuepathology.com), I've decided to dive deeper into the mainstream of the digital world!

I started the Blood Bank Guy website way back in 1998, initially as a way of connecting with the large numbers of people that attended the Osler pathology review course and heard me speak. At the time, what I was doing was pretty "cutting edge" (despite how silly it looks to me when I look back now!).

Over the years, I have become more interested in doing cool stuff on the site, but have been hampered by a lack of time. Recently, life has changed (I will write more about this later), and I find myself able to do more. I have started with podcasting, and have added both audio and video podcasts both to the site and through iTunes and YouTube. I've received some great feedback on the podcasts, and I believe that they are excellent ways to communicate topics to people that would rather hear or see stuff than read it. I've greatly expanded the quiz area, and am also expanding the glossary area. Both of these can serve as references for people that are studying blood banking. My future plans include animations for things like antibody identification (still figuring out whether to use HTML 5 or Flash).

This blog will include my general thoughts on things that pop up in the everyday practice of blood banking and transfusion medicine in a blood center. I am medical director for a large blood center in Denver, and things happen often that I wish I could share with you, but updating a web site is just too cumbersome. On the blog, I can quickly share events, situations, and learning points that hopefully will be of help. My mission, as always, is to teach basic transfusion medicine to as many as possible.

Thanks for checking out the blog! I hope that you will come back and visit often, and feel free to comment below! Click to return to bbguy.org.