Alloimmunization From Transfusions

Updated: Apr 05, 2016
  • Author: Eyal Oren, MD; Chief Editor: Michael A Kaliner, MD  more...
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Overview

Background

Allogeneic blood transfusion is a form of temporary transplantation. This procedure introduces a multitude of foreign antigens and living cells into the recipient that persist for a variable time. A recipient who is immunocompetent often mounts an immune response to the donor antigens, resulting in various clinical consequences, depending on the blood cells and specific antigens involved. The antigens most commonly involved are classified in the following categories: (1) human leukocyte antigens (HLAs), class I shared by platelets and leukocytes and class II present on some leukocytes; (2) granulocyte-specific antigens; (3) platelet-specific antigens (human platelet antigen [HPA]); and (4) RBC-specific antigens.

The consequences of alloimmunization to blood include the following clinical manifestations:

  • Alloimmunization against RBCs
    • Acute intravascular hemolytic transfusion reactions (rarely a consequence of alloimmunization and almost always caused by ABO antibodies) [1]
    • Delayed hemolytic transfusion reactions (DHTRs) (hemolysis caused by RBC alloantibodies at least 24 hours posttransfusion)
    • Hemolytic disease in newborns (mother's alloimmunization against fetal antigens, most often resulting from previous pregnancies)
  • Alloimmunization against platelets (platelet-specific or HLA class I antigens)
    • Refractoriness to platelet transfusion (an increase in the platelet count after platelet transfusion that is significantly lower than expected [eg, < 30% of predicted after 10-60 min or < 20% at 18-24 h posttransfusion])
    • Posttransfusion purpura (thrombocytopenia after transfusion of red cells or other platelet-containing products, associated with presence of platelet alloantibodies)
    • Neonatal alloimmune thrombocytopenia (mother's alloimmunization against fetal antigens, most often resulting from previous pregnancies)
  • Alloimmunization against granulocytes (granulocyte-specific or HLA antigens)
  • Refractoriness to granulocyte transfusion
    • Febrile nonhemolytic transfusion reactions
    • Transfusion-related acute lung injury (ie, a transfusion reaction in which donor HLA antibodies react against recipient antigens)
  • Transplant rejection
    • Alloimmunization against HLA antigens
    • Alloimmunization against blood cell antigens (in bone marrow transplantation)

Hemolytic transfusion reactions, posttransfusion purpura, febrile nonhemolytic transfusion reactions, and transfusion-related acute lung injury are discussed in Transfusion Reactions. Hemolytic disease in newborns and neonatal alloimmune thrombocytopenia are discussed in other sections of Medscape Reference. Transplant rejection is discussed in Assessment and Management of the Renal Transplant Patient.

DHTR and refractoriness to platelet transfusions are discussed in this article. Refractoriness to granulocyte transfusions involves either anti-HLA or granulocyte-specific antibodies and is similar to platelet refractoriness, except that refractoriness to granulocyte transfusions results in the patient failing to respond to the granulocyte transfusions. Because granulocyte transfusions are rarely used, they are not discussed further in this article.

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Pathophysiology

The main mechanism for alloimmunization to antigens present in transfused cells may involve presentation of the donor antigens by donor antigen–presenting cells (APCs), ie, monocytes, macrophages, dendritic cells, B cells, to recipient T cells. Recognition of the MHC class I alloantigens by CD4+ recipient T cells and their subsequent activation requires a co-stimulatory signal from either the donor or recipient APCs. Alloimmunization by non–leukoreduced platelets involves shared donor HLA antigens (HLA-restricted) and live functional donor APCs. The TH 2 subset of CD4+ T helper cells secretes interleukin (IL)–4, IL-5, IL-6, and IL-10; activates B cells; and initiates the antibody response. [2]

Leukoreduction of transfused platelets virtually eliminates donor APCs, but 20% of patients still develop alloimmunization. Alloimmunization from leukoreduced platelets involves recognition of the alloantigen and activation of recipient CD4+ T cells by alloantigen-presenting recipient APCs. This process also involves initial recognition of alloantigens by natural killer cells, which secrete interferon-gamma. This cytokine, in turn, is involved in the activation of CD4+ TH 2 cells.

After initial activation and development of the primary immune response, T cells become memory cells. Memory T cells do not need co-stimulatory signals to become activated and can recognize signals in the absence of class II HLA molecules. Thus, donor RBCs, platelets, and inactivated APCs can induce restimulation of the immune response. Blood transfusion (mainly through the TH 2 subset) can actively suppress the host immune response and induce tolerance to donor antigens. Another mechanism of immunosuppression involves stimulation of CD8+ suppressor T cells, which can recognize MHC class I alloantigens in platelets as well as donor APCs. Primary immunization with blood transfusion reflects the balance between clonal expansion and tolerogenic mechanisms. The secondary response depends on the restimulation of memory cells. Repeated immunization eventually results in sustained clonal expansion and clinically significant antibody production.

Refractoriness to platelet transfusions

The presence of HLA antibodies on the platelet surface is the most common cause of platelet refractoriness. Other non-HLA antigens present on the platelet surface (eg, platelet-specific antigens, HPA) are also involved in a number of cases. Patients not previously sensitized develop antiplatelet antibodies approximately 3-4 weeks (10-26 d) after the transfusion. Patients previously immunized by transfusion, pregnancy, or organ transplantation develop antiplatelet antibodies as early as 4 days after transfusion. Macrophages in the liver, spleen, and other tissues of the mononuclear phagocyte system phagocytize and destroy antibody-coated platelets.

Risk factors for developing antiplatelet antibodies include the presence of more than 1 million donor leukocytes in transfused products, transfusing ABO-mismatched platelets, the presence of an intact immune system (ie, absence of cytotoxic or immunosuppressive therapy), female sex (approximately 75% of cases), and a history of multiple transfusions (>20). [3]

Delayed hemolytic transfusion reactions

DHTRs occur between 24 hours and 3 months (frequently 2 wk) after transfusion and usually represent a secondary immune response in patients previously immunized by transfusion or pregnancy. [4] In very rare cases, brisk primary immune response can result in DHTR after an initial transfusion. Anti-RBC antibody titers frequently (about 50% of the patients with alloimmunization) drop below detectable levels, allowing incompatible units to be transfused. Transfusion with incompatible RBCs results in restimulation of memory cells and an increase in antibody titer. Antibodies bind to the surface of RBCs and, depending on the number of antigen-antibody interactions, activate complement with deposition of C3b. Usually, more than 105 antigenic sites per cell are required for potent complement activation.

Rarely, binding of immunoglobulin M antibodies to RBCs activates the classic complement pathway and leads to intravascular hemolysis. RBCs coated with immunoglobulin G antibodies and/or complement bind to C3b and immunoglobulin Fc receptors present on mononuclear phagocytes and are destroyed by phagocytosis (ie, extravascular hemolysis). Immunoglobulin G antibodies that efficiently activate complement (eg, those in Kidd and Duffy systems) tend to cause more intense extravascular hemolysis compared with antibodies that do not efficiently activate complement (eg, Rh and Kell).

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Epidemiology

Frequency

United States

Refractoriness to platelet transfusions

With regard to the frequency of alloimmunization, approximately 20-85% of patients who receive multiple transfusions become immunized against platelet antigens (eg, HLA, HPA), and approximately 30% of patients who are alloimmunized develop refractoriness to platelet transfusions.

Platelet refractoriness occurs in approximately 20-70% of patients who receive multiple transfusions. In approximately 66% of these patients, nonimmune factors (see Differentials) alone are the cause, whereas alloimmunization may be involved in 33% of refractory patients, often in combination with nonimmune causes.

With regard to the frequency of type of antibody involved in platelet refractoriness, HLA class I antibodies are involved in most alloimmunization cases, whereas platelet-specific antigens (ie, HPA) may be involved in approximately 10-20% of refractory cases. Combinations of both types of antibodies are involved in approximately 5% of cases. A single random RBC or platelet transfusion induces anti-HLA antibodies in less than 10% of recipients (most likely related to the tolerogenic effect of blood transfusions). If patients have more than 20 transfusions, they become sensitized in increasing proportions; after 50 transfusions, most (as many as 70%) patients have anti-HLA antibodies. Patients with RBC alloantibodies are more likely to have anti-HLA antibodies.

The presence of HLA antibodies shows better correlation with platelet refractoriness than antibodies directed against platelet-specific antigens. In the minority of cases of platelet refractoriness due to HPA antibodies, HPA-1b, HPA-5b, and HPA-1a antibodies are most commonly involved. Platelet-specific antigen systems are listed in Table 1.

Table 1. Human Platelet-Specific Antigen Systems (Open Table in a new window)

Platelet Antigen System Protein Antigen Synonyms Alleles Antigen Frequency
HPA-1 GPIIIa PlA,Zw HPA-1a = PlA1



HPA-1b = PlA2



97%



26%



HPA-2 GPIb Ko, Sib HPA-2A



HPA-2b



99%



14%



HPA-3 GPIIb Bak, Lek HPA-3a



HPA-3b



85%



66%



HPA-4 GPIIa Pen, Yuk HPA-4a



HPA-4b



>99%



< 1%



HPA-5 GPIa Br, Hc, Zav HPA-5a



HPA-5b



99%



20%



Delayed hemolytic transfusion reactions

Approximately 0.1-2% of patients who receive transfusions develop anti-RBC antibodies. In patients who are transfused regularly (eg, patients with sickle cell disease), the frequency of alloimmunization is much higher, affecting 10-38%. [5, 6] Despite the relatively high frequency of RBC alloimmunization, clinical manifestations of hemolytic transfusion reactions are rare (approximately 0.05% of patients transfused). The most frequent clinically significant RBC antibodies are shown in Table 2.

Table 2. Frequent Clinically Significant Anti-RBC Antibodies (Open Table in a new window)

Antigen System Frequency Among All Detected Alloantibodies Frequency of Antigen



(Whites)



Frequency of Antigen



(Blacks)



Potency*
E Rh 16-40% 30% 2% 4%
Kell (Kl) Kell 5-40% 9% 3% 9%
D Rh 8-33% 85% 92% 70%
c Rh 4-15% 80% 99% 4%
Jk(a) Kidd 2-13% 77% 91% 0.14%
Fy(a) Duffy 4-12% 63% 10% 0.46%
C Rh 2-10% 70% 32% 0.22%
e Rh 2-3% 98% 98% 1%
Jk(b) Kidd 2% 72% 43% 0.06%
S MNSs 1-2% 55% 31% 0.08%
s MNSs < 1% 89% 97% 0.06%
*Percentage of antigen-negative recipients who become alloimmunized if transfused with antigen-positive units

International

Clinically significant DHTR has been observed in about 1:2500 cases in Germany and 1:3000 cases in the Netherlands.

Mortality/Morbidity

See the list below:

  • The risk of death from a DHTR is approximately 1 fatality per 3.85 million units (1 per 1.15 million U in patients who have received transfusions).
  • Data regarding the impact of platelet refractoriness on morbidity and mortality for thrombocytopenic patients are inconsistent. Failure to achieve platelet counts greater than 5 X 10 9/L significantly increases the probability of life-threatening bleeding.

Race

Individuals from ethnic minority groups have an increased risk of alloimmunization from transfusion because notable differences exist in the frequency of blood cell antigens between races. Efforts to increase the blood supply from minority donors are essential to reduce the frequency of alloimmunization in these groups.

Sex

DHTRs and platelet refractoriness are more common in females than in males, possibly because of previous sensitization from pregnancy.

Age

Older patients (ie, >50 y) tend to have reduced immune responsiveness to blood transfusions.

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