Authors: Gwen Clarke, MD, FRCPC; Jacqueline Côté, MLT; and Debra Lane, MD, FRCPC
Publication date: August 2017, updated September 2018
Anti-M is an antibody directed to an antigen of the MNS blood group system. The M antigen is located on the red blood cell surface glycoprotein known as glycophorin A.
Anti-M may be naturally occurring (i.e. arising without stimulus by transfusion or pregnancy related red blood cell exposure) or can be an immune stimulated antibody. In either case, it is predominantly an IgM antibody with some associated IgG component and often occurs in association with other antibodies. If a “new” anti-M is found in a prenatal patient, it is not unusual to find at delivery that the baby is M negative. This is presumptive evidence that the anti-M seen prenatally in the maternal plasma is naturally occurring and not immune stimulated.
In the context of transfusion, anti-M is considered clinically insignificant for most patients. It does not typically contribute to acute or delayed hemolytic transfusion reactions. An exception is anti-M in some patients with sickle cell disease. In this context, anti-M can contribute to hemolysis or even trigger hyper hemolysis.
Anti-M is very rarely associated with hemolytic disease of the fetus and newborn (HDFN).
Routine donor antigen typing (phenotyping) at Canadian Blood Services does not include M typing. Requests for M negative red blood cell units therefore result in additional manual phenotyping.
Patient management: Pre-transfusion testing
When anti-M is detected in a patient’s pre-transfusion sample testing, it is generally considered to be a clinically insignificant antibody. Usually there is no requirement for selection of M antigen negative donor red blood cells. Instead, red blood cell units that are crossmatch compatible to the IAT stage or equivalent using IgG antihuman globulin should be selected for transfusion.
Anti-M may react in gel IAT methods and lead to an incompatible crossmatch. If this happens, saline tube IAT (SIAT) may be used to find compatible units.
When the patient has an antibody that is broadly reactive or pan reactive and it is not possible to “rule out” anti-M, then donor red blood cells that are phenotypically similar to the patient’s red blood cell antigens may be selected. Typically this includes red blood cell units negative for the same clinically significant antigens that the patient lacks. When selecting phenotype-matched red cells for transfusion, the Rh, Kell, Kidd and Duffy blood group systems are considered along with the S antigen. The M antigen is not usually considered when seeking phenotypically matched red blood cells. If possible, crossmatch compatible donor units to the IAT or equivalent test would also be selected from among those found to be phenotypically similar.
If IAT crossmatch compatible units are difficult to find, an IAT prewarm technique can sometimes be helpful. Often, anti-M reacts best at room temperature or 4 °C, even if there is an IgG component to the antibody. Prewarm techniques may diminish or eliminate anti-M reactivity and allow for a compatible crossmatch.
For patients undergoing therapies which induce hypothermia, including some cardiac surgical procedures, providing M negative units for patients with anti-M is recommended by some transfusion services. There is no evidence to support this requirement.
Sickle cell patients
For sickle cell patients without antibodies, most guidelines recommend transfusion of Rh and Kell matched units. For those patients with one or more antibodies, complete donor phenotype matching is often recommended. Typically, this matching includes the Rh, Kell, Kidd and Duffy blood group systems along with the S antigen, and not M matching.
For sickle cell patients with an identified anti-M, however, M negative red blood cell units should be provided, in addition to phenotyping that otherwise matches the patient red blood cell antigen and antibody profile. Anti-M in this clinical context can be associated with hemolytic reactions; therefore, assuring compatibility by providing M antigen negative red cells is required.
Patient management: Prenatal testing
Anti-M is a common antibody detected in prenatal samples. Most often it is not clinically significant as it is predominantly an IgM antibody which does not cross the placental barrier.
To distinguish IgM from IgG anti-M, some antibody identification methods exist that exclude IgM antibodies. In addition, special techniques such as DTT treatment of plasma may help distinguish between the two. When the anti-M is determined to be an IgG antibody that reacts at 37 °C, and has a high or rising titer, it may be considered a clinically significant antibody and the paternal partner should be tested for the M antigen. The mother’s prenatal serological anti-M levels are monitored with regular antibody titration during the antenatal period. An approach to monitoring anti-M antibodies has been suggested that involves intermittent titration to detect rising titers with regular follow-up titration in only those cases that demonstrate increasing antibody levels.
Only very rarely does anti-M reach a critical titer necessitating a referral to maternal-fetal medicine for further fetal monitoring. Recent literature suggests that anti-M may act through fetal erythroid suppression rather than through hemolysis. This may result in neonatal onset anemia rather than fetal anemia. Canadian Blood Services prenatal reports generally recommend that antigen M positive neonates born to mothers with anti-M antibodies should be clinically monitored for late onset anemia at 3 – 6 weeks post-delivery. The specific comment provided on prenatal reports is: Anti-M may cause suppression of fetal erythropoiesis. It is recommended that the baby be monitored for symptoms of late-onset anemia up to 2 months of age. Ref: Trans Med Rev 2014; 28:1-6.
Occasional case reports of severe intrauterine fetal anemia due to anti-M can be found. This is very exceptional, however, and despite the relatively common detection of anti-M in pregnant women, significant fetal or neonatal anemia is very unusual in North America.
Reid M, Lomas Francis C and Olsson M. The Blood Group Antigens Facts Book. MNS Blood group System. Page 67.
Fung M, Grossman B, Hillyer C, Westhoff C. AABB Technical Manual, 18th Ed. Chapter 14: Other Blood Groups; M, N, S, s and U antibodies and their clinical significance. Page 343.
Daniels G. Human Blood Groups 3rd ed. 2013. Chapter 3: MNS Blood Group System, 3.18.3: Clinical Significance of anti M and anti N. Page 137.
Working Party of the BCSH Blood Transfusion Task Force. Guidelines for compatibility procedures in blood transfusion laboratories. Transfusion Medicine 2004; 14, 59 – 73.
NHS Blood and Transplant. NHSBT: Specification SPN214/3: The Clinical Significance of Blood Group Alloantibodies and the Supply of Blood for Transfusion. http://hospital.blood.co.uk/media/27446/spn2143-the-clinical-significance-of-blood-group-alloantibodies-and-the-supply-of-blood-for-transfusion.pdf
Yasuda H, Ohto H, Nollet KE, Kawabata K, Saito S, Yagi Y, Yutaka N, Ishida A. Hemolytic disease of the fetus and newborn with late-onset anemia due to anti-M: a case report and review of the Japanese literature. Transfusion Medicine Reviews 2014; 28 (1): 1-6.
Davis, Allard, Qureshi et al. for BCSH. Guidelines on red cell transfusion in sickle cell disease. Part I: principles and laboratory aspects. http://www.b-s-h.org.uk/guidelines/guidelines/red-cell-transfusion-in-sickle-cell-disease-part-l/
Skeate, S and Goldman, M. Phenotype matching for sickle cell patients: A review and recommendations for transfusion practice. https://professionaleducation.blood.ca/en/transfusion/publications/phenotype-matching-sickle-cell-patients-review-and-recommendations
Canadian Blood Services Diagnostic Services. Year In Review 2015. https://blood.ca/en/hospital/diagnostic-services-reports
The Canadian Haemoglobinopathy Association (CanHaem). Consensus Statement on the Care of Patients with Sickle Cell disease in Canada. 2016. http://sicklecellanemia.ca/pdf_2016/CANHAEM.pdf
Issitt, P. Applied Blood Group Serology, 4th edition. 1998. Page 463.
Kurtz SR, Ouellet R, McMican A, and Valeri DR. Survival of MM red cell during hypothermia in two patients with anti M. Transfusion 1983; 23:37-39.
Jain MD, Cabrerizo-Sanchez R, Karkouti K, Yau T, Pendergrast JM, Cserti-Gazdewich CM. See and you shall find – But then what do you do? Cold agglutinins in cardiopulmonary bypass and a single-center experience with cold agglutin screening before cardiac surgery. Transfusion Medicine Reviews 2013; 27:65-73.
Stetson B, Scrape S, Markham KB. Anti M alloimmunization: Management and outcome at a single institution. Am J Perinatol Rep 2017; 7: 205 – 210.