The Vel blood group is a human blood group that has been implicated in hemolytic transfusion reactions.^[1] The blood group consists of a single antigen, the high-frequency Vel antigen, which is expressed on the surface of red blood cells. Individuals are typed as Vel-positive or Vel-negative depending on the presence of this antigen. The expression of the antigen in Vel-positive individuals is highly variable and can range from strong to weak. Individuals with the rare Vel-negative blood type develop anti-Vel antibodies when exposed to Vel-positive blood, which can cause transfusion reactions on subsequent exposures.^[2]

The Vel blood group is associated with the SMIM1 gene, which is located in the 1p36 region of chromosome 1.^[3][4] This gene produces small integral membrane protein 1, a single-pass transmembrane protein which carries the Vel antigen^[2] but whose structure and function are otherwise poorly understood.^[5] The Vel-negative phenotype is inherited in an autosomal recessive manner, being expressed by patients who are homozygous for a deletion mutation in the coding region of SMIM1 which renders the gene nonfunctional.^[5][6] Patients who are heterozygous for this mutation, meaning inherited from only one parent, exhibit weakened Vel antigen expression.^[7] Missense mutations at nucleotide position 152 can also result in a weak Vel phenotype, and various single nucleotide polymorphisms in the noncoding regions of SMIM1 affect the strength of Vel antigen expression.^[5]

The Vel-negative blood type is rare. The highest prevalence of Vel-negative blood has been reported in Sweden, where approximately 1 in 1200 individuals exhibit this phenotype.^[5] Only about 1 in 3000 English people^[8] and 1 in 4000 Southern Europeans are Vel-negative, and much lower rates have been reported in people of African and Asian heritage.^[5]

When exposed to Vel-positive blood through transfusion or pregnancy, Vel-negative individuals can become sensitized and begin producing an anti-Vel antibody. If they are exposed to Vel-positive blood again, the anti-Vel antibody can bind to Vel-positive red blood cells and destroy them, causing hemolysis.^{[2][9]: 696} Anti-Vel is a particularly dangerous antibody because it is able to activate the complement system, which causes immediate and severe destruction of red blood cells.^[10][11] Therefore, patients with anti-Vel should not be transfused with Vel-positive blood, as it can cause a serious acute hemolytic transfusion reaction.^[2][8] Finding compatible blood for Vel-negative patients is difficult due to the rarity of this blood type,^[5] and it may be necessary to perform autologous blood donation or to contact rare blood banks.^[12]

Cases of anti-Vel causing hemolytic disease of the newborn (HDN) have been reported, but this is an unusual occurrence.^[5][8] It is hypothesized that anti-Vel associated HDN is rare because the antibody is usually predominantly composed of IgM immunoglobulin, which does not cross the placenta into the fetal circulation.^[9]: 981 In addition, the expression of Vel is very weak on fetal red blood cells – particularly in children who are heterozygous for Vel.^[8]

Autoimmune hemolytic anemia (a condition in which patients produce antibodies against antigens on their own red blood cells, leading to hemolysis)^[9]: 956 involving auto-anti-Vel has been reported.^[8]

An individual's Vel blood type can be determined by serologic methods, which use reagents containing anti-Vel antibodies to identify the antigen, or by genetic testing.^[5] As of 2019, serologic testing for Vel is mainly performed using polyclonal antibodies isolated from the blood of patients with anti-Vel. However, this method is problematic because these antibodies are variable in quality and sometimes produce false negative results in patients with weak Vel expression; moreover, the reagent cannot be mass-produced.^[5][13] In 2016, a recombinant monoclonal antibody against Vel was introduced^[14] and it has since been used to screen for Vel-negative blood donors in France.^[5] Genotyping of SMIM1 using polymerase chain reaction is another method that has been used to identify Vel-negative donors.^[15]

Anti-Vel is a mixture of IgG and IgM immunoglobulins and is able to activate complement, which can cause hemolysis in vitro (i.e. during compatibility testing).^[5][16] Anti-Vel can be mistaken for a typical cold antibody in compatibility testing if inappropriate techniques are used; this misidentification is dangerous, because such antibodies are usually clinically insignificant.^[5][12][17]

The Vel blood group was first described in 1952 by Sussman and Miller,^[18] who reported a case of a patient who had suffered a severe hemolytic reaction following a blood transfusion.^[2] The patient's serum was subsequently crossmatched against blood samples from 10,000 donors, and only five of them were found to be compatible, indicating that an antibody against a high-frequency antigen was present.^[5] This antigen was named Vel after the first patient.^[1] The authors also observed variable expression of the antigen: the patient's serum reacted less strongly with the blood of her children, who were presumably heterozygous for Vel, than with blood from unrelated donors.^[5]

In 1955, a further case was described ^[19] in which the blood of a woman who had suffered a transfusion reaction was incompatible with more than 1,000 donors, but not with the blood of the first Vel-negative patient.^[5] This patient's antibody was the first example of an anti-Vel that could hemolyze red blood cells in vitro.^[20] Six other individuals from three generations of this woman's family were found to be Vel-negative, but they did not exhibit an anti-Vel antibody, demonstrating that anti-Vel is not naturally occurring.^[2] By 1962, 19 cases of anti-Vel and approximately 50 cases of Vel-negative patients had been described.^[20]

Although the Vel blood group has been widely studied due to its significance in transfusion medicine, its genetic and molecular basis remained unclear for several decades.^[12][14] In 2013, two research groups simultaneously identified the SMIM1 gene and its protein product as the determinants of the Vel blood group.^[12][3][4] The Vel blood group was officially recognized by the International Society of Blood Transfusion in 2016.^[7]