Anti-LW vs Anti-D

Not to be confused with Lutheran or Lewis, Anti-LW antibodies, named after Karl Landsteiner and Alexander Wiener, are generally thought to be nuisance antibodies in the transfusion medicine world, with little impact on clinical outcomes to patients in regard to transfusion and Red Cell survival. However, their true identification is important for certain populations of people, such as pregnant women. 

Anti-LW antibodies often manifest with an Anti-D pattern on antibody screen / panels. The reason for this is that LW glycoproteins are expressed at an increased rate on Rh positive Red Blood Cells. It is posited that the LW glycoprotein actually requires interaction with the Rh proteins to properly express itself on the Red Blood Cell. Thus Rh negative cells express little to no LW glycoprotein. As a result, RhD positive cells will usually react much stronger with an Anti-LW antibody. RhD negative cells will usually react much weaker or not at all depending on LW expression. So we can see that, even though LW and RhD antigens are not related from a genetic standpoint, they are phenotypically related in that they may produce apparent Anti-D reactivity. 

The LW blood group system (also potentially known as ICAM4 or Intercellular Adhesion Molecule-4) consists of 3 known antigens -- LWa, LW(b), and LWab. LWa is extremely common (greater than 90% of most populations). LWb is a low frequency antigen, and LWab even less. 

Most anti-LW antibodies are IgG in nature and generally exist as an autoantibody. They are not known to activate compliment. Allo-Anti-LW is extremely rare but has been known to occur in only a few patients, those who are Lwa(-)Lwb(-) are most at risk of developing an alloantibody. 

Anti-Lw antibodies are often seen in certain populations where expression of Lw antigens is transiently suppressed. Some pregnant women and those with certain hematologic malignancies may suppress their Lw expression, this can cause a temporary Anti-Lw(a) or Anti-Lw(ab) to be produced. It has been observed that the antibody reactivity clears up once pregnancy or disease state has passed. 

Allo Anti-Lw  has been implicated in a single known potential instance of HDFN, which was relatively mild. Cases of autoanti-Lw do not result in hemolytic transfusion reactions. However, to obtain a compatible crossmatch, it may be necessary to transfuse Rh negative blood, given Lw expression is lower on Rh negative cells. Transfusion of RhD positive cells likely would not result in hemolysis or decreased RBC survival, but each transfusion center will have its own rules on how it deals with Anti-Lw transfusion.  

Why is it important to differentiate between D and LW?

Anti-LW will usually present itself in an RhD positive patient with a positive autocontrol and positive Direct Antiglobulin Test (IgG/Coombs). 

Knowing whether it is a real Anti-D vs Anti-LW is important for transfusion requirements, as well as for pregnant mothers. If someone has a partial D antigen, it is possible for them to create an Anti-D while still showing as RhD positive. Once the Anti-D is created, they must received RhD negative blood, because this is a real allo-Anti-D create in response to the immune system seeing epitopes of the RhD antigen not made by the recipient. 

Likewise, it is important to know whether a pregnant mother has or does not have an Anti-D, as this can affect whether or not they receive RhD isoimmunization prophylaxis through the use of Rho(D) immune globulin, such as RhoGAM. Misidentifying an Anti-LW could lead to a mother not receiving this prophylaxis which could potentially result in RhD isoimmunization down the line causing HDFN is future offspring. 

How do you differentiate between D and LW?

Most hospital Blood Banks are not going to have LWa/LWb,LWab antisera or similar. There are indeed some tests that a normal hospital Blood Bank may be able to perform to differentiate between D and LW. 

For those hospitals at that perform DTT (Dithiothreitol) testing on Daratumumab (Anti-CD38) patients to "see underneath" the non-specific pan-agglutination that Anti-CD38 therapy causes, you already have a valid test in house! 0.2M DTT will denature the LW antigens but will NOT denature the RhD antigen. If LW is suspected, after DTT treatment of selected RhD positive cells, panel reactivity should be significantly reduced or outright removed. This is a sign that the LW antigens were disrupted. 

Additionally, for those that do not perform DTT testing, but do receive umbilical cord blood for newborn testing, this can be used as a differentiator tool as well. Cord Blood exhibits high level of LW antigen expression regardless of RhD status. Thus, comparing to reactivity against adult RhD negative cells vs newborn RhD cells should show a difference. The adult cells should barely or not react at all, whereas the newborn RhD negative cells should still show quite a strong positive.