Alloimmunization From Transfusions

Updated: Sep 08, 2017
  • Author: Douglas Blackall, MD, MPH; 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 may mount an immune response to the donor antigens (ie, alloimmunization), resulting in various clinical consequences, depending on the blood cells and specific antigens involved. The antigens most commonly involved can be classified into 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 antigens [HPAs]); and (4) RBC-specific antigens.

The consequences of alloimmunization to blood-based antigens 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 typically presenting clinically 7–14 days after transfusion)
    • Hemolytic disease of the fetus and newborn (mother's alloimmunization against red blood cell 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 10-60 min posttransfusion or < 20% at 18-24 h posttransfusion])
    • Posttransfusion purpura (thrombocytopenia after transfusion of red cells or other platelet-containing products, associated with the presence of platelet alloantibodies)
    • Neonatal alloimmune thrombocytopenia (mother's alloimmunization against fetal  platelet antigens, most often resulting from previous pregnancies but can be seen in a first pregnancy)
  • 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 with recipient white blood cell antigens)
  • Transplant rejection
    • Alloimmunization against HLA antigens
    • Alloimmunization against blood cell antigens in bone marrow transplantation leading to hemolysis and the possibility of delayed engraftment

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.

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

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Pathophysiology

The immunologic mechanism for alloimmunization to antigens present in transfused cells involves 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 II alloantigens by CD4+ recipient T cells and their subsequent activation requires a co-stimulatory signal from either the donor or recipient APCs. The TH 2 subset of CD4+ T helper cells secretes interleukin (IL)–4, IL-5, IL-6, and IL-10, which activates B cells and initiates the antibody response. [2]

Leukocyte reduction of transfused platelets virtually eliminates donor APCs, but patients may still develop alloimmunization. Alloimmunization from leukocyte-reduced cellular blood products requires recognition of the alloantigen by recipient APCs and activation of recipient CD4+ T cells. This process also involves the 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. Interestingly, 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 thus reflects a balance between clonal expansion and tolerogenic mechanisms. A secondary immune 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

HLA alloimmunization is the most common cause of platelet refractoriness. The immune response to non-HLA antigens, present on the platelet surface (most importantly, platelet-specific antigens or HPAs) are involved less commonly. Patients not previously sensitized may develop platelet antibodies approximately 3-4 weeks after transfusion. However, patients previously immunized by transfusion, pregnancy, or organ transplantation may develop platelet 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 platelet antibodies include the presence of more than 1 million donor leukocytes in transfused cellular blood products (platelets, red blood cells), 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 generally occur 1-2 weeks after transfusion. They represent a secondary immune response in patients previously immunized to a red cell antigen by transfusion or pregnancy. [4] In very rare cases, a brisk primary immune response can result in a DHTR after an initial transfusion. When RBC antibody titers drop below detectable levels (about 50% of the patients with alloimmunization), there is a risk for the transfusion of incompatible units of blood. Transfusion with incompatible RBCs results in restimulation of memory cells and an increase in IgG antibody titer (ie, an anamnestic immune response). Antibodies bind to the surface of RBCs and, depending on the number of antigen-antibody interactions, may activate complement with deposition of C3b. Typically, more than 105 antigenic sites per cell are required for potent complement activation.

RBCs coated with IgG antibodies and/or complement bind to immunoglobulin Fc or C3b receptors present on mononuclear phagocytes and are destroyed by phagocytosis (ie, extravascular hemolysis). IgG antibodies that efficiently activate complement (eg, those in the Kidd blood group system) tend to cause more intense extravascular hemolysis compared to antibodies that do not efficiently activate complement (eg, Rh and Kell system antibodies). Rarely, binding of IgM antibodies to RBCs activates the classic complement pathway and leads to intravascular hemolysis, but this is much more commonly seen in the context of ABO-incompatible transfusions with accompanying acute hemolytic transfusion reactions.

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Epidemiology

Frequency

Refractoriness to platelet transfusions

Approximately 20-85% of patients who receive multiple transfusions become immunized to platelet antigens (eg, HLA, HPA), and 30% of patients who are alloimmunized develop refractoriness to platelet transfusions.

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

HLA class I antibodies are implicated in most alloimmunization cases, while platelet-specific antigens (ie, HPA) may be involved in 10-20% of refractory cases. Combinations of both types of antibodies are seen in approximately 5% of cases. A single random RBC or platelet transfusion induces HLA antibodies in less than 10% of recipients (most likely related to the tolerogenic effect of blood transfusions). However, if patients receive more than 20 transfusions, they become sensitized in increasing proportions. As an example, after 50 transfusions, most patients (as many as 70%) have HLA antibodies. In addition, patients with RBC alloantibodies are more likely to have HLA antibodies.

The presence of HLA antibodies is better correlated with platelet refractoriness than antibodies directed against platelet-specific antigens. In those cases of platelet refractoriness due to HPA antibodies, HPA-1b, HPA-5b, and HPA-1a antibodies are most commonly implicated. The 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 red blood cell transfusions develop RBC antibodies. In patients who are transfused regularly or in whom there is a mismatch between donor and recipient red blood cell antigens (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), as blood banks routinely detect RBC antibodies and provide antigen-negative units of blood for transfusion. The most frequently detected clinically significant RBC antibodies are shown in Table 2. [32]

Table 2. Frequent Clinically Significant 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% 22% 4%
K Kell 5-40% 9% 2% 9%
D Rh 8-33% 85% 92% 70%
c Rh 4-15% 80% 96% 4%
Jk(a) Kidd 2-13% 77% 92% 0.14%
Fy(a) Duffy 4-12% 66% 10% 0.46%
C Rh 2-10% 68% 27% 0.22%
e Rh 2-3% 98% 98% 1%
Jk(b) Kidd 2% 74% 49% 0.06%
S MNSs 1-2% 55% 31% 0.08%
s MNSs < 1% 89% 94% 0.06%
*Percentage of antigen-negative recipients who become alloimmunized if transfused with antigen-positive units

Clinically significant DHTRs have been observed in about 1:2500 transfused patients in Germany and 1:3000 transfused patients in the Netherlands.

Mortality/Morbidity

The risk of death from a DHTR is approximately 1 fatality per 3.85 million red blood cell units transfused.

Data regarding the impact of platelet refractoriness on morbidity and mortality for thrombocytopenic patients are inconsistent. However, failure to achieve platelet counts greater than 5 X 109/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 group 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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