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Autoimmune Hemolytic Anemia - 12/27/2012

posted Dec 27, 2012, 7:29 AM by Rohit Das   [ updated Dec 27, 2012, 8:22 AM by Purnema Madahar ]

Anemia…of the hemolytic variety; such was the topic of the report yesterday, and thus my topic for today’s daily. I wanted to talk specifically about autoimmune hemolytic anemia (AIHA), and also some physiologic tidbits that I found interesting as I read about this topic…so:

·         Anemia that becomes symptomatic often presents with dyspnea…why?

·         When should you suspect hemolysis, and how do you subsequently evaluate for it?

·         What’s the pathophysiology behind AIHA, and how is it diagnosed?

·         What are some important management aspects of AIHA…particularly around blood transfusions?

Anemia that becomes symptomatic often presents with dyspnea…why?

·         This question might seem straightforward, and I suppose it is to some degree. Nevertheless, I think it’s important to understand the dynamics of oxygenation, as it applies to several other disease states as well. So – I propose to you the following equations:

DO2 (Oxygen Delivery) = CO (Cardiac Output) X Arterial O2 Content

Arterial O2 Content = (Hg X 1.36 X Arterial O2 Saturation) + PaO2

·         As per the latter equation, arterial oxygenation is mainly dependent on hemoglobin, as oxygen dissolved within our blood provides a negligible contribution. So – decreased Hg (anemia) leads to decreased arterial oxygen content, which in turns leads to poor oxygen delivery…

·         But, does it really matter? Well, it depends. Under normal circumstances, oxygen delivery far outweighs oxygen demand from peripheral tissues. Even under circumstances of poor oxygen delivery due to anemia, human physiology has developed clever compensatory mechanisms - we can “extract” oxygen more efficiently (remember the Bohr effect??...2,3-BPG and all that…yea, it’ll start coming back to you…) and augment oxygen delivery via increasing cardiac output (thus tachycardia…).

·         At rest, through all these mechanisms, adequate oxygenation can be maintained at hemoglobin levels as low as 5!! Exertion is a different story. The above mechanisms become overwhelmed, leading to symptoms. Importantly, the exact mechanism by which one becomes dyspneic is not particularly defined. There is some literature to suggest that peripheral muscle tissue contain “ergoreceptors,” which sense local tissue hypoxia and acidosis and consequently set off neural mechanisms which lead to dyspnea….a lot of hosh-posh at this point, but I hope this provides some understanding of why anemia, especially acutely, is important physiologically…

When should you suspect hemolysis, and how do you subsequently evaluate for it?

·         Hemolysis should be suspected in anyone presenting with relatively rapid onset of worsening exertional tolerance, pallor and jaundice. History should focus on a detailed medication history, prior blood transfusions, infectious syndromes…among many other things.  Important things to look for on exam are conjunctival rim pallor (at a Hg cutoff of 8, +LR of 4.5, -LR of 0.5), confirming jaundice by examination of the sclera/tongue/skin, a thorough cardiovascular exam, and looking for organomegaly.

·         Ultimately, laboratory data are required for confirmation…I’d hope you know the most important findings – indirect hyperbilirubinemia (total to direct ratio of ~0.2), high LDH, elevated reticulocyte count (median of 9% in patients hemolyzing) and low haptoglobin. In one study, the combination of a high LDH and low haptoglobin was 95% specific for hemolysis, and vice versa, 92% sensitive. Examination of the smear is also imperative, as it helps to distinguish between different etiologies.

·         Important caveat – one can be hemolyzing, and not be anemic. Normal bone marrow is able to compensate for a maximum RBC turnover of 5% RBC mass/day (normal turnover is 1%/day). So, if the rate of hemolysis is less than that, anemia will not be present. I think in this context, the above adjunct laboratory data become more valuable.

·         Hemolytic anemia is NOT a diagnosis; rather, it is a sign of some other underlying disease. The differential for hemolysis is extremely broad, but conceptually can be put into an intracorpuscular or extracorpuscular etiology. To avoid what is already going to be a lengthy discussion, I’m going to focus on the diagnosis pertinent to our patient – AIHA.

What’s the pathophysiology behind AIHA, and how is it diagnosed?

·         The issue underlying AIHA is implied by its name – our immune system, for some ungodly and unclear reason, decides to make antibodies against membrane antigens on our own red blood cells. AIHA is not terribly rare, having an incidence of 1-2% per year. It can be idiopathic (50% of cases) or associated with a secondary etiology, like immune diseases (SLE, Anti-phospholipid syndrome, IBD), malignancies (CLL, Non-Hodgkin’s Lymphomas), infections (EBV, CMV, HIV, Mycoplasma among others) or various drugs. Actually, the patient presented at report had a concurrent history of HIV/AIDS – a review article on HIV-related AIHA is attached.

·         AIHA is subdivided into the “warm” (WAIHA) and “cold” (CAIHA) types, with the former being much more common (90% versus 10%). They are so defined because warm antibodies cause RBCs to agglutinate at body temperature (37oC), whereas cold antibodies agglutinate below that (generally 4oC to 30oC). Some other important differences:

o   WAIHA is due to IgG autoantibodies, which fix complement, but not well enough to cause intravascular hemolysis. IgG coated RBCs are taken up by spleen macrophages, partially digested and expelled as “spherocytes,” which are rigid and destroyed within the uncompromising sinusoids of the spleen.

o   CAIHA is due to IgM autoantibodies, which fix complement very well, but only in very high titers. That scenario is rare and only really occurs in clonal malignancies. In the absence of high titers, IgM does not bind cytoxic cells well, and so are overall very inefficient in causing hemolysis. So, CAIHA is a rare cause of significant hemolytic anemia. Patients with chronic CAIHA have an indolent course, typically have worsened symptoms/signs in the colder parts of the year, and don’t really require much therapy other than a friend to give them a nice, warm hug (okay, maybe a bit more than that)…

·         AIHA is diagnosed by the Direct Coomb’s Test (called the DAT in most labs – Direct Antiglobulin Test). The DAT is pretty straightforward. Patient RBCs are washed, leaving them coated with complement +/- autoantibodies (depending on their avidity and titer). They are then incubated with anti-IgG and anti-complement – subsequent agglutination = a positive Coomb’s test. Some important facts:

o   Not uncommonly is AIHA DAT-negative (4-5% of cases). More often, the DAT may only be positive with anti-CD3, since the autoantibody may be present in low titers, or have poor avidity to their antigen (which is often the case in drug-induced AIHA). In the case of CIAHA, since anti-IgM is generally not present in the reactant, positivity solely occurs from anti-CD3.

o   DAT is positive in 10% of hospitalized patients who have no evidence of hemolysis; thus it is very nonspecific outside the context of hemolytic anemia. Moreover, titers do not correlate with risk or severity of AIHA.

o   The majority of cases of AIHA are dominated by a warm OR cold autoantibody…but sometimes both can occur, which seems to be more often the case in malignancies and infections (particularly HIV).

What are some important management aspects of AIHA…particularly around blood transfusions?

·         Giving blood to patients with AIHA is somewhat of a slippery slope. The main issue is that it is very difficult to identify compatible units, as autoantibodies interfere with the ability to identify alloantibodies. Advanced identification methods are needed, which takes time…time that one usually does not have. The bottom line – if you need to give blood, type it and give it ASAP. An observational study of 53 consecutive patients showed that despite being given incompatible blood, there were no indicators of subsequent increased hemolysis. Theoretically, though incompatible, they’re not destroying donated blood any faster than their own…

·         Adjunctive treatments are based on case series and retrospective data, i.e., expert recommendations. These include steroids (1mg/kg/day), and in refractory cases splenectomy (which is not effective for CAIHA since most of the extravascular hemolysis occurs in the liver) and/or rituximab. Various other immunosuppressive medications have been tried, with variable efficacy.

·         AIHA can be a fatal illness, but there aren’t very good estimates on its overall mortality. Most patients (estimated to be around 80%) will need to be on chronic steroids to avoid recurrence. Often, AIHA heralds the onset of other diagnoses, like systemic autoimmune diseases (SLE, Antiphospholipid Syndrome) or lymphoproliferative malignancies. It is also a significant risk factor for VTE events, especially in the context of SLE.

Well, that does it for this year…I’ll be off the floors next month, and so your life will most likely be devoid of the daily until February – use the time to catch up. I’ve reorganized the names of this year’s posts, such that that if you double click on “Newsletters,” the topics are now indexed alphabetically.

Just want to collectively thank the readers who have expressed their appreciation – it keeps me going. Have a Happy New Year!

Autoimmune Hemolytic Anemia
Gehrs et. al., AmJ Hematology 2002, Volume 69: 258-71

Saif, AIDS Pt CARE 2001, Volume 15 (4): 217-24